Abstract
Autophagy is a dynamic self-renovation biological process that maintains cell homeostasis and is responsible for the quality control of proteins, organelles, and energy metabolism. The E1-like ubiquitin-activating enzyme autophagy-related gene 7 (ATG7) is a critical factor that initiates classic autophagy reactions by promoting the formation and extension of autophagosome membranes. Recent studies have identified the key functions of ATG7 in regulating the cell cycle, apoptosis, and metabolism associated with the occurrence and development of multiple diseases. This review summarizes how ATG7 is precisely programmed by genetic, transcriptional, and epigenetic modifications in cells and the relationship between ATG7 and aging-related diseases.
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Introduction
Autophagy is essential for the degradation and reutilization of proteins1 and transforms various cytoplasmic cargo (e.g., microbes, organelles, and cytotoxic protein aggregates) into smaller molecules to energize cell metabolism and maintain the renewal of organelles2. During this process, the cytoplasmic components are isolated into double-membrane structures named autophagosomes, transported to lysosomes, and degraded3.
Aging is a popular topic in human health research. Although it is an unavoidable physiological process, it is also the spatiotemporal background of many diseases, including neurodegenerative diseases, diabetes, skeletal muscle atrophy, and tumors. Recent studies have shown that autophagy plays an important role in aging and the occurrence and development of aging-related diseases.
Approximately 40 autophagy-related genes (Atgs) are part of the autophagy machinery. Atg7 is an essential autophagy-related gene that encodes a series of proteins of ~630–700 residues in length found in various eukaryotes4. ATG7 is a homodimeric E1 enzyme that drives ATG8 and ATG12 to their own E2 enzymes, ATG3 and ATG10, respectively5. The 3D structure of the C-terminal domains of the dimer is shaped like the body of a bird, with the ATG-binding N-terminal domains similar to wings5,6. The interactions between ATG7 and the E2 core domain of ATG3 and ATG10 are markedly similar across different species7. ATG7 is also associated with multiple biological functions beyond the activation of autophagy8. We found that ATG7 modulates p53 activity to regulate the cell cycle and survival during metabolic stress. ATG7 also plays important roles in protein lipidation events similar to ubiquitination and membrane fusion events during autophagy9. This protein is critical to several processes, including the precaution of axonal neurodegeneration10, the preservation of hematopoietic stem cells11, and adipose differentiation12 (Figs. 1 and 2).
Atg7 is highly conserved among different species.
ATG7 protein is a homodimeric E1 enzyme that mediates covalent modifications of other autophagy-related proteins during autophagy, including the binding of ATG5 and ATG12, and the lipidation of LC3.
Regulation on ATG7 and its relationship with aging-related diseases
Regulation of the Atg7 gene
Atg7 variants and gene fusion
Previous studies in multiple Atg7 knockout (KO) animal models investigated the relationship between Atg7 and altered biological processes (Table 1). Several additional studies focused on genetic alterations in Atg7 and their impact on aging-related diseases. A putative G-quadruplex-forming sequence folds into a four-stranded G-quadruplex (G4) structure in the first intron of Atg7. This structure always appears in guanine-rich DNA sequences, regulating gene replication and transcription in cancer cells and neurons13. G4-ligand pyridostatin can form 1:1 and 2:1 complexes with G4 in Atg7, inhibiting autophagy by stabilizing the G4-DNA complex14. Another distinct G4-DNA-binding ligand, BRACO19, can downregulate Atg7 transcription. The formation and disassociation of Atg7 G4-DNA is the original pathway for regulating autophagy in neurons, which correlates with the effect of age on memory15.
Nineteen DNA sequence variants (DSVs) containing single-nucleotide polymorphisms (SNPs) have been observed in the Atg7 gene promoter of coronary artery disease patients, including those with acute myocardial infarction (AMI). Multiple DSVs and SNPs alter the transcriptional activity of the Atg7 promoter by affecting the combination of transcription factors and Atg7 expression16. Genome-wide association studies and DNA methylation and exome sequencing data have identified 41 variants, 56 SNPs, and 38 SNPs of Atg7 associated with HDL-cholesterol, systolic blood pressure, and blood pressure, respectively17. Moreover, Atg7 variant rs8154 is a new prognostic marker for breast cancer based on in silico analysis18.
Parkinson’s disease (PD) is a fast-growing neurological disorder and neurodegenerative disease19. Reduced Atg7 transcriptional activity was observed with four novel heterozygous variants and confirmed in five PD patients. Variations in the Atg7 gene promoter alter ATG7 protein levels in PD patients and influence autophagic activity, possibly contributing to the onset of the disease20. Furthermore, elevated plasma ATG7 levels in the Han population of South China may result in susceptibility to late-onset sporadic PD21. An SNP in the Atg7 gene can also impact the age of Huntington’s disease (HD) onset22. A European HD Network study demonstrated the impact of Atg7 V471A polymorphism on the age of HD onset on Italians23.
Transcription factors and transcriptional regulators
The prominent transcription factor forkhead box O1 (FOXO1) is the main target of insulin signaling and is involved in interleukin-9 (IL-9) signaling pathways. FOXO1 is also a transcription-independent mediator of autophagy24,25. FOXO1 is acetylated by its dissociation from SIRT2, which determines its interaction with ATG7 and promotes autophagy under serum starvation24,26. The Ac-FOXO1-ATG7 complex activates autophagy independent of Beclin1 or Mechanistic target of rapamycin (mTOR)24. Under low oxidative stress (OS) conditions, FOXO1 maintains cell viability via its export from the nucleus, acetylation into Ac-FOXO1, and formation of the Ac-FOXO1-ATG7 complex. Under high OS levels, FOXO1 is located in the nucleus, promoting the transcription of proapoptotic proteins and apoptosis27. Most FOXO1 DNA-binding domain mutants preserve their interaction with cytoplasmic ATG728. Moreover, the interaction between ATG7 and phosphorylated FOXO1 in the cytoplasm of immature natural killer (NK) cells is essential for NK cell maturation29,30. The FOXO1-ATG7 complex is also associated with bone formation and bone-related disorders31.
FOXO3, another Atg7 transcriptional regulator, is predicted to bind Atg7 at the ENCODE H3K4Me1 site 850 bp upstream of the Atg7 transcription start site. FOXO3a-transactivated ATG7 acts as a tumor suppressor in non-small cell lung cancer (NSCLC) and mediates CK1α-induced autophagy, an anti-neoplastic mechanism32. Additionally, cellular redox imbalance and mitochondrial dysfunction in Atg7-KO mouse embryonic fibroblasts (MEF) cells are partly abrogated by FOXO1/3 overexpression through the restoration of antioxidant enzymes and reactive oxygen species (ROS) suppression33.
Heat shock factor 1 (HSF1) is a transcription factor and main regulator of temperature stress responses implicated in tumorigenesis34. HSF1 can directly bind to the promoter of Atg7 to increase its expression, which is necessary for the cytoprotective autophagy induced by chemotherapeutic agents35. Furthermore, miR-217 induces HSF1/ATG7 pathway signaling by limiting NF1 expression and enhancing breast cancer cell autophagy, leading to chemoresistance36. During starvation, PSMD10 transfers to the nucleus and cooperatively binds to the Atg7 gene promoter with nuclear HSF1 to upregulate ATG7 expression37. NBAT1 suppresses Atg7 transcription by promoting PSMD10 degradation and inhibits PSMD10 and HSF1 occupancy on the Atg7 promoter, inhibiting autophagy and chemoresistance in NSCLC38.
Transforming growth factor-β1 (TGF-β1) is a cytokine that increases the expression of autophagy-related genes, including Atg739. TGF-β1 function is partly mediated by its regulation of Y-box binding protein 1 (YB-1), which binds to the Atg7 promoter. The nuclear translocation of YB-1 induced by TGF-β1 promotes Atg7 transcription and participates in the liver injury40. TGF-β1 is also a common fibrosis marker involved in multiple diseases. TGF-β1 and ATG7 play roles in fibrosis in many tissues in an autophagy-dependent manner. During maladaptive kidney repair, autophagy stimulates fibrogenesis by fibroblasts via the pro-fibrotic factor, fibroblast growth factor 241. In contrast, ATG7-mediated autophagy suppresses vocal fold injury-induced fibrosis42. The TGF-β1/ATG7 axis is also involved in fibrosis in unilateral ureteral obstruction, SiO2-induced pulmonary inflammation, and radiation-induced skin injury, making autophagy a potential therapeutic target in fibrosis43,44,45.
Signal transducer and activator of transcription (STAT) 3 is activated by phosphorylation and forms homo- or heterodimers. It binds to the Atg7 promoter, upregulating ATG7 expression. The IL-6/Janus kinase (JAK)/STAT3 pathway modulates skeletal muscle atrophy by regulating ATG7-mediated autophagy46. The inhibition of STAT3-mediated autophagy by ATG7 might be a novel target in triple-negative breast cancer47 and denervation-induced muscle atrophy48. Autophagy can increase the expression of pro-inflammatory cytokines, including IL-6 and IL-849,50. These reports indicated that ATG7 might connect autophagy and inflammation.
Retinoid acid receptor is a transcription factor that can bind to the 5’-flanking region of the Atg7 proximal promoter, regulating ATG7 transcription and hepatocellular carcinoma (HCC) progression51. CAMP response element-binding protein (CREB) is a transcriptional regulator that binds to the Atg7 promoter at the −1809 to −1412 region. P38/Hsp27/CREB/ATG7 pathway signaling affects HCC chemoresistance by regulating autophagy52. Transcription factor NRF1 stimulates the Atg7 promoter53, promoting autophagy in human nucleus pulposus cells54. Besides raising Atg7 mRNA levels, EVI1 can also increase intracellular ROS levels involved in EVI1-induced autophagy. Therefore, EVI1 might promote drug resistance via dual control of ATG755.
DNA methylation of Atg7 gene
DNA methylation modulates multiple biological functions, including signal transmission, DNA repair, and gene expression56. Legionella Infection can irreversibly change the GATC motif to G(6 mA)TC in the Atg7 promoter region, causing a time-dependent reduction in Atg7 mRNA, which further inhibits autophagosome formation. These findings about host defense against Legionella, including autophagy, might help prevent and treat Legionnaires’ disease57.
Atg7 was one of five hub DNA methylation-regulated genes in the Framingham heart study. Studies in monocytes and peripheral blood leukocytes showed that the Atg7 methylation and expression status might be a novel epigenetic mechanism for coronary heart disease (CHD)58. The indirect methyltransferase inhibitor adenosine dialdehyde decreases Atg7 expression and autophagy in cancer cells, indicating that Atg7-related methylation might be a potential target for treating breast and lung cancer59. Another study aimed at finding epigenetic alternations in miRNAs and DNA through an in silico approach identified Atg7 as a hub gene and a potential target for gestational diabetes mellitus (GDM) diagnosis and treatment60.
Regulation on Atg7 mRNA
Modification and regulation of Atg7 mRNA have been widely discussed in recent decades, including methylation and regulation by miRNA, lncRNA, circRNA, and RNA-binding proteins. The impact of these influential factors on Atg7 can further affect multiple physiological processes and aging-related diseases (Table 2).
M6A-methylation
N6-methyladenosine (M6A) methylation is a common internal modification in eukaryotic mRNA61. M6A influences almost every fundamental aspect of mRNA metabolism and is controlled by RNA-binding proteins (RBPs), methyltransferase complexes, and demethylases. M6A targeting of Atg5 and Atg7 regulates adipogenesis by affecting autophagy. Atg5 and Atg7 are two potential targets of the fat-associated RNA demethylase, FTO62. Methyltransferase-like 3 (METTL3)-mediated M6A can attenuate Atg7 mRNA stability, decreasing its expression and facilitating cellular aging and osteoarthritis by regulating the autophagy-GATA4 axis. Specifically, METTL3-mediated M6A initiates the decay of the Atg7 transcript in a YTH M6A RNA-binding protein 2-dependent way63. Silencing METTL3 enhances Atg7 mRNA stability and increases its expression. Synovium-targeted METTL3 siRNA downregulates senescence-associated secretory phenotype expression and increases autophagy in osteoarthritis-fibroblast-like synoviocytes, further alleviating cellular senescence in joints and destabilization of the medial meniscus-induced cartilage destruction63. METTL3 can regulate Atg7 to reverse drug resistance in chronic myelocytic leukemia cells and gefitinib resistance in NSCLC cells caused by β-elemene64,65. In addition, Atg7 M6A is increased in GDM with obesity66.
miRNAs
miRNAs belong to a highly conserved family that controls its downstream gene translation processes67. Several miRNAs have Inhibitory effects on Atg7 in heart disease. Heart failure is a chronic disease associated with cardiomyocyte apoptosis and autophagy. MiR-129-5p inhibits autophagy and cardiomyocyte apoptosis, retarding heart failure progression68. MiR-143 expression relieves myocardial ischemia/reperfusion (I/R) injury by downregulating Atg7 expression69. miR-182-5p and miR-20b-5p play a similar role70,71. Indeed, MiR-27a-5p could inhibit Atg7 and had a cardioprotective effect against hypoxia-induced H9c2 cell injury, suggesting it is a potential strategy for healing hypoxia-related heart disease72. MiR-542-5p might also be a target for treating heart disease caused by hypoxia/reoxygenation-induced cardiomyocyte injury due to its relationship with Atg7 mRNA73. Adipose-derived stromal cell-derived exosomes enhanced by miR-93-5p have cardioprotective effects after AMI in an Atg7-targeting pathway that inhibits autophagy and inflammatory response74. Similarly, miR-188-3p regulates autophagy and myocardial infarction by altering Atg7 expression75. Moreover, atherosclerosis (AS) is also under the control of miR-188-3p by targeting Atg776. MiR-221 negatively regulates FOXO3, inhibits Atg7 transcription, and is a potential target for cardiac fibrosis after myocardial infarction (MI)77. The loss of cardiomyocytes after an injury, such as MI, might be compensated by cardiac progenitor cells; miR-143 participates in this process via targeting Atg778. Studies in the Se-deficient chicken model showed that Se deficiency upregulates Atg7 expression and inhibits cardiomyocyte autophagy by modulating miR-17-5p expression79.
Emerging studies have shown that miRNAs can directly inhibit Atg7 in some key pathways involved in drug resistance in cancer. MiR-7-5p increases chemoresistance to cisplatin (DDP) in bladder cancer by suppressing invasion and inhibiting Atg7 expression80. TRIM65 knockdown in A549/DDP cells downregulates autophagy and DDP resistance via the miR-138-5p/Atg7 axis81. Similarly, miR-4486 inhibits autophagy and decreases DDP resistance in HCT116/DDP and SW480/DDP cells by targeting Atg782. MiR-1236-3p also regulates autophagy and DDP resistance via its effects on Atg7 mRNA expression83. MiR137 attenuates starvation-induced autophagy and promotes adriamycin sensitivity in U87 cells by regulating Atg7 expression84. MiR-615-3p and miR-17 may regulate Atg7 expression and further chemoresistance in NSCLC85,86. In addition, the miR-3657/Atg7 axis increases the sensitivity of gastric cancer cells to apatinib87.
MiR-375 binds to a particular site within the 3’ untranslated region of Atg7 mRNA, decreasing HCC cell viability under hypoxic conditions88,89. Additionally, autophagy in HCC cells is inhibited by miR-490-3p in an Atg7-targeting pathway90. Apigenin is a possible chemosensitizer in HCC and sensitizes BEL-7402/ADM cells to adriamycin via the miR-520b/Atg7 axis91. The proliferation and invasion of HCC cells are similarly modulated by miR-181a-5p, miR-222-3p, and miR-37592,93,94. Atg7 is a confirmed target of the miR-17 seed family, and Atg7 inhibition by the miR-17 seed family (e.g., miR-20a and miR-17) has been reported in prostate cancer95. Furthermore, miR-17 negatively regulates Atg7 expression and modulates autophagy in T98G glioblastoma cells96. Moreover, the viability of glioma cells is partly under the control of miR-20a97, while purple sweet potato delphinidin-3-rutin regulates the regulatory function of miR-20b-5p through the protein kinase B (AKT)/Creb/miR-20b-5p/Atg7 pathway98.
MiR-186 can decrease Atg7 and Beclin1 expression levels, thereby inhibiting autophagy in glioma-conditioned human cerebral microvascular endothelial cells99. MiR-96 in prostate cancer cells has a biphasic effect on autophagy by inhibiting mTOR or Atg7, which means the inhibition or ectopic overexpression both abolishes hypoxia-induced autophagy100. MiR-93 expression is negatively correlated with Atg7 expression and increased in dopamine agonist-resistant prolactinomas101. MiRNA-93 downregulates Atg7 and enhances cabergoline resistance of prolactinoma102. Along with clinical staging of neuroblastoma progression, miR-20a-5p expression decreases whereas its target Atg7 increases103. MiR-106a can decrease Atg7 levels and suppress the death of colorectal cancer cells104. MiR-210, an Atg7-targeting miRNA, can strongly enhance lung cancer cell proliferation, while another Atg7-targeting miRNA, miR-138-5p, inhibits the invasion and self-renewal of lung cancer stem-like cells105,106. MiR-190A, miR-582-5p, and miR-154 can increase the progression and drug resistance in bladder cancer cells by inhibiting Atg7107,108,109. Breast cancer is also regulated by Atg7-relevant miRNAs, including miR-1275 and miR-348110. Epithelial ovarian cancer (EOC) is regulated by Atg7-inhibiting miRNA, miR-6881-3p111. Other cancer types are also affected by the interaction between Atg7 and miRNAs, including lymphoma via the hsa-miR-6511b-5p/Atg7 axis112, pancreatic cancer (PC) through the miR-766-5p/Atg7 axis113, retinoblastoma via miR-154-5p/Atg7114, and thyroid cancer through the miR-1343-3p/Atg7 axis115.
MiRNAs also regulate Atg7 in various aging-related diseases. A significant increase in miR-654-5p and its inhibition of Atg7 were observed in degenerated nucleus pulposus tissues from intervertebral disc degeneration (IDD) patients116. In IDD nucleus pulposus, miR-202-5p overexpression reduces Atg7 levels, while miR-202-5p inhibition enhances autophagy and reduces apoptosis in nucleus pulposus cells117. Melatonin enhances Atg7 transcription and translation by inhibiting miR-106a-5p in annulus fibrosus cells in disc degeneration patients118. MiR-192-5p reduction increases Atg7 expression and inhibits vascular smooth muscle cell (VSMC) proliferation and migration. Therefore, serum miR-192-5p may be a novel diagnostic biomarker for atherosclerosis (AS)119. Another related miRNA, miR-508-5p, inhibits Atg7 expression and blocks autophagy in endothelial cells, which is important for AS procession120. In addition, the interactions between miRNAs and Atg7 may regulate ischemic brain injury121, cerebral I/R injury122,123, neuronal apoptosis124, M. tuberculosis infection125,126, allergic asthma127, systemic lupus erythematosus128, sepsis129 and sepsis-induced acute kidney injury (AKI)130, nonobstructive azoospermia131, urethral stricture and urethral fibrosis132, hypoxia-induced pulmonary hypertension133, hepatic I/R injury134, hepatitis B virus replication135, inflammatory bowel disease136, diabetes mellitus137, pancreatic ductal adenocarcinoma (PDAC)138, and senile cataracts139.
LncRNAs
LncRNAs are long-stranded noncoding RNA with a length greater than 200 nucleotides. LncRNA exerts various effects by binding to DNA, RNA, and proteins140. LncRNA APF regulates autophagy and myocardial infarction by targeting miR-188-3p, which directly binds with Atg775. Autophagy mediated by the lncRNA H19/miR-143/Atg7 signaling axis relieves myocardial I/R injury under 6-Gingerol treatment conditions69. In addition, lncRNA CHRF enhances autophagy and exacerbates myocardial ischemia/reperfusion injury by modulating the miR-182-5p/Atg7 pathway70. LncRNA TUG1, which is induced by E26 transformation-specific proto-oncogene 2 (ETS2), sponges miR-129-5p to increase Atg7 expression. Ets2-KO inhibits Atg7 mediate-autophagy and postpones the development of heart failure68. LncRNA 0003250 regulates miR-17-5p, which alters the Atg7 expression and is correlated with Se deficiency79. Multiple molecular pathways in HCC are regulated not only by miRNA but also by upstream lncRNAs. The proliferation and invasion of HCC are regulated by lncRNA TINCR, which modulates the miR-375/Atg7 axis94. LncRNA DANCR sponges miR-222-3p and promotes Atg7 expression to accelerate HCC proliferation and autophagy93. Similarly, lncRNA CCAT1 regulates Atg7 by sponging miR-181 in HCC92.
LncRNA RASSF8-AS1 regulates autophagy by targeting miR-188-3p, which increases Atg7 levels and may be a novel target for the prevention and prognosis of AS76. The lncRNA nicotinamide nucleotide transhydrogenase-antisense RNA1 via miR-1236-3p/Atg7 axis increases DDP resistance in lung cancer83. Many other physiological processes are regulated in this manner, such as the lncRNA SNHG8/miRNA-588/Atg7 axis in colorectal cancer141, lncRNA HULC/Atg7 axis in epithelial ovarian carcinoma142, lncRNA PVT1/miR-186/Atg7 axis in glioma vascular endothelial cells123, lncRNA GAS8-AS1/miR-1343-3p/Atg7 axis in thyroid cancer115, lncHOTAIR/hsa-miR-6511b-5p/Atg7 axis in lymphoma112, lncHOTAIR/miR-20b-5p/Atg7 axis in hepatic I/R injury134, lncRNA SNHG3/miR-485/Atg7 axis in brain I/R injury123, Lnc-FSD2-31:1/miR-4736/Atg7 axis in PDAC138, and lncRNA WAC-AS1/miR-192-5p/Atg7 axis in hepatitis B virus replication135.
CircRNAs
CircRNAs are novel RNA molecules characterized by covalently closed loops widely present in eukaryotes143. In EOC, circ-EEF2 promotes autophagy by interacting with miR-6881-3p and upregulating its target Atg7111. CircRNA RACGAP1 is a sponge for miR-3657 to upregulate Atg7 expression, and circRACGAP1 knockdown increases the sensitivity of gastric cancer cells to apatinib87. CircRNA0006948 modulates Atg7 expression levels through the CircRNA0006948/miR-490-3p/Atg7 pathway, which regulates the invasion, proliferation, and migration of osteosarcoma144. CircRNA0092276 regulates the miR-348/Atg7 axis to promote autophagy and the doxorubicin resistance in breast cancer110. Autophagy-associated circAtg7 is located in both the nucleus and cytoplasm. Nuclear circAtg7 is a scaffold that strengthens the interaction between Atg7 mRNA and human antigen R protein to stabilize Atg7 mRNA. Cytoplasmic circAtg7 is a sponge for miR-766-5p that increases Atg7 expression. Furthermore, circAtg7 regulates PC cell proliferation and metastasis by modulating autophagy113.
Atg7 is involved in other pathways, including the chr10:115386962-115390436+/miR-6914-5p/Atg7 axis in inflammatory bowel disease136, circ-ADAM9/miR-20a-5p/Atg7 axis in diabetes mellitus137, circHIPK3/miR-190b/Atg7 axis in atherosclerosis145, circPAN3/miR-221/Atg7 axis in cardiac fibrosis77, circHIPK3/miR-20b-5p/Atg7 axis in myocardial I/R injury71, and Hsa_circ_0004058/miR-186/Atg7 axis in senile cataract139.
Others
RBPs interact with RNA directly via specific RNA-binding domains and participate in many post-transcriptional regulatory processes. The RBP HuR binds to the coding region of Atg7 mRNA to regulate hypoxia-induced autophagy146. Additional mechanistic studies showed that HuR increases Atg7 mRNA stability by binding to its AU-rich elements147. This interaction mainly occurs in patients with diabetic intervertebral disc degeneration or under hypoxia conditions146,147. RBP LIN28A also interacts with Atg7 mRNA, which might be the target for LIN28A regulation at the post-transcriptional level. This interaction can increase Atg7 mRNA stability and protein levels and promote chemoresistance in breast cancer148.
U2AF35 belongs to the splicing factor SR gene family, which is frequently mutated in various diseases. Recurrent mutations in U2AF35 (S34F) have been observed in myelodysplastic syndrome and tumors and promote transformation by generating aberrant Atg7 pre-mRNA 3’ ends. In U2AF35(S34F)-transformed cells, the Atg7 pre-mRNA is processed incorrectly, leading to secondary mutations149.
Post-translational modifications of the ATG7 protein
ATG7 can be modulated during autophagy by several post-translational modifications, including acetylation, deacetylation, and ubiquitination.
Acetylation and deacetylation
The p300 acetyltransferase regulates the acetylation of various autophagy proteins. Disruption of p300 can reduce ATG7 acetylation and stimulate autophagy, while p300 overexpression increases ATG7 acetylation and inhibits starvation-induced autophagy150. BCL2-associated athanogene 6 (BAG6)/HLA-B-associated transcript 3 increases p53 acetylation and limits the p300-dependent acetylation of ATG7151. Additionally, BAG6 tightly controls p300 intracellular localization, influencing the accessibility of p300 to ATG7 and p53 and controlling autophagy151,152. Under various pathophysiological conditions, the beta chain of the non-classical MHC-II protein HLA-DM restricts the human T-cell leukemia virus type-1 (HTLV-1) expression by directly interacting with ATG7 and regulating ATG7 acetylation promoted by p300153. A histone acetyltransferase encoded by the M. oryzae ortholog of GCN5 acetylates ATG7, downregulating light- and nitrogen-starvation-induced autophagy in response to important environmental changes131.
The NAD-dependent deacetylase Sirt1 regulates autophagy and the cellular starvation response154. Sirt1 mediates chondrocyte autophagy by physically interacting with and deacetylating ATG7155. Osteoarthritis (OA) is an age-related degenerative disorder accompanied by pain and joint mobility disturbances. Sirt1 levels decrease in aged or OA cartilage compared to young and healthy cartilage. Sirt1 deacetylates the lysine residues on ATG7 and other crucial autophagy proteins to increase autophagy in chondrocytes. Chondrocyte-specific Sirt1 silencing decreases chondrogenic markers. Thus, Sirt1 is a potential target for OA intervention156. Aldehyde dehydrogenase 2 (ALDH2)-enhanced Sirt1 modulates the interaction between LC3 and ATG7. ALDH2 activation in aging hearts enhances LC3 deacetylation in the nucleus and the formation of LC3-ATG7 complexes in the cytoplasm by controlling Sirt1 activation and nuclear localization157.
ATG7 is also involved in the Sirt1/p53 signaling pathway. As a transcription factor, p53 regulates miR-155 expression, and miR-155 directly targets the Sirt1 3’UTR region. Under high-glucose conditions, the p53/miR-155/Sirt1/ATG7 mediates autophagy and could be a potential therapeutic target for diabetic kidney injury158 (Fig. 3).
It has been reported that ATG7 is regulated by epigenetic modifications of acetylation, deacetylation, and ubiquitination. p53/miR-155/Sirt1 axis forms a autophagy-regulating loop with ATG7.
Ubiquitination
The ubiquitination of proteins plays a role in proteasome degradation, immune response regulation, mitochondrial autophagy, epigenetic regulation, and apoptosis159. Recent studies have indicated that the RING-type E3 ligase, tripartite motif-containing protein (TRIM) 7/RNF90, promotes ATG7 ubiquitination. TRIM7 is a core factor in infection-, starvation- and rapamycin-induced autophagosome accumulation. It helps host cells resist bacterial infection by inducing the K63-linked ubiquitination of ATG7 at K413 to positively regulate autophagy. Moreover, experiments in mouse models have shown that ATG7 ubiquitination at K413 or K409 has a decisive impact on L. monocytogenes infection and host cell resistance. Autophagosome accumulation after L. monocytogenes infection of wild-type cells but not cells with TRIM7 or ATG7 inactivating mutations clears intracellular bacteria and exerts defensive effects160.
Oxidative stress-induced autophagy helps prevent cell damage and maintains cellular homeostasis161. Previous studies have shown that ROS activates the ataxia-telangiectasia mutated (ATM)-cell cycle checkpoint kinase 2 (CHK2) pathway and promotes autophagy. When the ATM/CHK2 pathway is activated by ROS, ATM and CHK2 phosphorylation leads to TRIM32 phosphorylation at S55, activating its E3 ubiquitin ligase function. TRIM32 activation causes ATG7 K63-linked ubiquitination at K45, initiating ROS-induced autophagy. In addition, Liu et al. showed that the ATM/CHK2/TRIM32/ATG7 axis might alleviate I/R injury in mice by activating autophagy162.
ATG7 functions and its relationship with aging-related diseases
ATG7 plays a crucial role in two ubiquitin-like conjugation systems involving ATG12 and LC3163. The ubiquitin-like conjugation system involving ATG12 also contains ATG7, ATG5, ATG16, and ATG10; the ATG12-ATG5-ATG16 complex forms an E3 ligase6,7. ATG7 catalyzes another ubiquitin-like conjugation system with ATG3 and ATG4 for the lipidation of LC3164. On this basis, the classical autophagy function and related regulatory mechanism of ATG7 are involved in several physiological processes and aging diseases. Several studies have indicated that ATG7 has additional functions beyond autophagy.
Autophagy-dependent functions of ATG7
Cell fate
Theoretically, autophagy and apoptosis are crucial catabolic processes regulating cell maintenance and tissue homeostasis165. ATG7 promotes apoptosis, prevents epithelia-mesenchymal transition (EMT), and inhibits proliferation by blocking aerobic glycolysis in the mitochondria of triple-negative breast cancer (TNBC) cells166. Studies with human periodontal ligament cells also demonstrated that ATG7 overexpression contributes to the proliferation and inhibits apoptosis in aging cells167. Autophagy is renoprotective during AKI, especially in vancomycin (Van)-induced AKI168. Researchers found that the cell death-related gene, PKC-δ, was markedly suppressed in the Atg7-KO model after Van treatment. ATG7 might induce renal cell apoptosis after Van treatment by binding to PKC-δ168.
TNFAIP8 interacts with the ATG7-ATG3 complex and facilitates LC3 lipidation. The TNFAIP8-ATG7 interaction is important in regulating autophagy and proliferation in liver cancer cells169.Alzheimer’s disease (AD) is a common neurodegenerative disorder mainly caused by β-amyloid (Aβ) peptide accumulation. Estrogen receptor β can promote autophagy by interacting with ATG7, which further improves the autophagy-lysosomal activity in Aβ clearance and decreases the risk of AD170.
ATG7 regulates the cell cycle and thrombopoiesis during hematopoiesis, counteracting hematopoietic aging and leukemogenesis at multiple stages. ATG7-dependent canonical autophagy is critical for hematopoietic stem cells, but not for differentiated or somatic cells171. Atg7-KO mice are more prone to engrafted leukemogenesis, demonstrated by increased white blood cells, lymphocytes, and platelets. ATG7 deletion causes the deterioration of hematopoietic stem and progenitor cell (HSPC) function, which may lead to leukemogenesis172. Additional mouse studies revealed that the loss of ATG7 in HSPCs led to a lethal pre-leukemic phenotype173. Autophagy is implicated in the cell cycle of HSPCs in a nutrient-dependent manner; the absence of ATG7 leads to the ablation of the HSCPs cell cycle174. Transcriptomic analysis of HSPCs suggested that hematopoietic ATG7-related autophagy defects caused elevation of iron activity, inhibited osteocyte differentiation and calcium metabolism, potentially leading to bone loss and osteoporosis175. Atg7-deficient models had mitochondrial and cell cycle dysfunction, impaired platelet production, and failed hemostasis176. In addition, abolishing ATG7-related autophagy in the hematopoietic system greatly impacts the aging of non-hematopoietic organs177.
Reduced osteoblast differentiation is critical in bone-related pathogenesis, including OA and osteoporosis. Ferutinin significantly increases the expression of KLF2, ATG7, and several other autophagy-related proteins in dental pulp-derived stem cells. In contrast, Atg7-or Beclin1-KO reduces KLF2 and the levels of osteoblast (OB) differentiation-related molecules, indicating that ferutinin regulates OB differentiation via KLF2 and autophagy178. ATG7 and superoxide dismutase 2 are involved in the pathogenesis of osteoporosis, and their expression levels correlated in osteoporotic mice and osteoporosis-free mice179. Another study using dexamethasone-induced osteoporotic mouse models suggested that glucocorticoid-induced bone loss enhanced ATG7-related autophagy in osteoclasts via the PI3K/Akt/mTOR signaling pathway180.
Cell structure and development
The lamellar body (LB) is a specific lysosome-related organelle in type 2 alveolar epithelial cells, specifically related to autophagy181,182. Atg7-KO in mice interrupts the maturation process of LB and the production of surfactant protein B, indicating that ATG7 is necessary for the formation, maturation, and maintenance of LB183. In addition, suppression of AMP-activated protein kinase-mediated autophagy leads to poor lung development or even bronchopulmonary dysplasia184.
Increased ATG7 in neural tubes promotes neural crest cell delamination by suppressing the BMP4/Smad signaling pathway. Moreover, ATG7 overexpression accelerates cell progression toward S phase185. Additionally, research using ATG7 heterozygous mice suggested that ATG7 is involved in progeria by modulating autophagy186.
ATG7 regulates cerebrovascular development by promoting endothelial fibronectin expression and modulating Protein kinase A activity. Atg7-endothelial knockout (eKO) reduces fibronectin expression and causes cerebral astrocyte-microvascular disassociation, impairing the blood-brain barrier homeostasis187. ATG7 deletion leads to frustration in epinephrine-stimulated von Willebrand factor (VWF) secretion accompanied by prolonged bleeding time. Moreover, the processing, maturation, and secretion of VWF in endothelial cells is controlled by ATG7-mediated autophagy188. In chick embryos, ATG7 expression is observed in the plexus vessels of angiogenesis, and interruption of autophagy blocks angiogenesis by altering cell viability and migration189. Ethanol exposure can enhance autophagy by upregulating LC3 and ATG7 expression levels. After ethanol treatment, the incidence rate of congenital cardiovascular diseases in chick embryos increases190 High-glucose levels increase ATG7 and LC3 expression, indicating that autophagy may also be involved in high-glucose-induced cardiovascular malformation191.
ATG7 prevents EMT by suppressing aerobic glycolysis166. During EMT, epithelial cells lose their cell polarity, resulting in higher mesenchymal phenotypes that might affect the progression of malignant tumors derived from epithelial cells192. Altered ATG7 expression levels correlate with tumor progression and prognostic outcomes in TNBC166. In Atg7-KO retinal pigment epithelium (RPE) cells, the epithelial marker claudin-1 is reduced, while mesenchymal markers are decreased, leading to cell migration and enhanced contractility. ATG7-mediated autophagy is a notable mechanism in EMT resistance193. Research with chicken embryos has shown that ATG7 affects whole embryonic development by regulating EMT. During EMT in gastrulation, ATG7 expression is observed on the top of the endoderm and ectoderm. E-cadherin, a marker of EMT, increases when ATG7 is overexpressed194.
Others
It has been reported that ATG7(−/−) mitochondria have deficiencies in mitochondrial respiration. Reduced resting mitochondrial oxygen consumption, increased compensatory basal glycolytic rates, and increased steady-state ROS levels have been observed in ATG7(−/−) cells. Pancreatic beta cell-specific Atg7-KO mice exhibit mitochondrial dysfunction along with oxidative stress, indicating the important role of ATG7 in glucose metabolism195. Impaired ATG7-mediated autophagy enhances muscle loss and sarcopenia in the aging population, and betaine can regulate autophagy to stop degeneration in aged muscle196. Moreover, a proteotoxic heart failure study suggested that ATG7-induced autophagy could decrease cardiac hypertrophy and interstitial fibrosis, ameliorate ventricular dysfunction, and reduce intracellular aggregates197. In addition, the regulation of nuclear factor-kappaB (NF-κB) by ATG7 can also affect drug resistance in cancer cells. The blockade of ATG7-mediated autophagy interrupts IκB degradation by inhibiting cathepsin D, which further activates the NF-κB signaling pathway, which can influence the drug sensitivity of cancer cells198.
Autophagy-independent functions of ATG7
Cell fate
The transcription factor p53 is a key tumor suppressor that plays fundamental roles in cancer immunity and inflammation199. It is also involved in many cellular functions, including metabolism, DNA repair, cell cycle arrest, cell differentiation, senescence, and cell death200. Previous studies have shown a significant relationship between p53 and autophagy-related proteins, especially ATG7201,202. The absence of ATG7 can increase mitochondrial ROS and DNA damage, affect cell cycle inhibitor p21 expression, and reciprocally regulate p53-dependent cell cycle and cell death pathways by activating p53. These observations demonstrated reciprocal regulation in which ATG7 can bind to and regulate p53 and further modulate the cell cycle and survival during metabolic stress203. Cnot-3, a component of the CCR4-NOT complex, can shorten the poly(A) tail of Atg7 mRNA. ATG7 and p53 co-immunoprecipitate from Cnot3-KO heart lysates, showing that these two proteins interact. Additional research indicated that the nuclear ATG7 and p53 levels increased in Cnot3-KO cells compared to wild-type cells, and nuclear ATG7 modulated p53 activity to induce the expression of cell death-promoting factors204. A recent study showed that ATG7, p53, and VIM3 form a complex in prostate cancer and BPH-1 cells. Moreover, the VIM3/p53/ATG7 complex affected the migration of prostate cancer cells by binding with the pri-miR-371a-3p promoter, providing a novel method of prostate carcinoma differentiation205.
Metabolic reprogramming
The Warburg effect is a special energy metabolic process first described in cancer cells. This effect is frequently found in cancer tissues and many other rapidly dividing normal cells206. Autophagy provides a mechanism by which cells can cope with energy crises and is associated with energy metabolism in tumor cells. ATG7 inhibits the Warburg effect by binding PKM2 and preventing its phosphorylation on Tyr-105 by FGFR1207. Loss of ATG7 produces the opposite result, promoting EMT in tumor cells. The link between ATG7 and the Warburg effect could provide new strategies for cancer treatment207.
NF-κB
Research has shown that ATG7 exerts its effects by regulating transcription. The proangiogenic activity of ATG7 in the brain is mediated by IL-6 production, which is dependent on NF-κB208. Atg7-eKO can alleviate brain inflammatory responses after I/R in mice. Atg7-eKO reduces IKKβ phosphorylation, which inactivates NF-κB and decreases the mRNA levels of several pro-inflammatory cytokines, including IL-6 and IL-8. Interestingly, transcriptional regulation by ATG7 is independent of its role in autophagy209.
Inflammation and ATG7 have a complicated relationship in bone disease. Inflammation inhibits autophagy, proliferation, and the cell cycle in chondrocytes, manifested by arrest in G1, a reduced S phase, and downregulation of ATG7, ATG5, p62, and LC3. Inhibiting the PI3K/AKT/mTOR signaling pathway relieves inflammatory responses in OA rat models210. Increased Grb2-associated-binding protein-2 (GAB2) in chondrocytes correlates with OA progression in in vivo and in vitro OA models. Furthermore, GAB2 inhibition decreases p62 expression but increases the expression of ATG7 and other autophagy-related proteins211.
Others
ATG7 is also essential for counteracting hematopoietic aging. Knocking out Atg7 or Atg5 showed that ATG7 plays a non-autophagic role in maintaining normal nucleosome assembly and decelerating aging in the CD11b(+)Ly6G(−) cell population in the bone marrow. ATG7 deletion significantly confers an aging phenotype on this blood lineage subgroup. These results indicate a dual role for ATG7 in resisting hematopoietic aging212. In addition, ATG7 promotes OCT4 transcription and stem-like properties by interacting with and stabilizing β-catenin. This mechanism may promote the cancer stem-like cell characteristics of prostate cancer, including tumor initiation, self-renewal, and drug resistance213.
Summary and future directions
ATG7, an E1-like ubiquitin-activating enzyme, promotes the formation and extension of autophagosome membranes, thus initiating cellular autophagy. The basic autophagy-dependent functions of ATG7 involve two ubiquitin-like conjugation systems—ATG12-ATG5 and LC3-phosphatidylethanolamine. Besides its E1-like effects in autophagy, whether ATG7 could serve as an E1 enzyme in ubiquitination reactions needs to be clarified.
ATG7 protein is involved in many aging diseases and could serve as a promising therapeutic target (Fig. 4). Importantly, ATG7 plays different roles in various tissues. Muscle-specific deletion of ATG7 downregulates muscle mass and strength and causes abnormal mitochondria and swollen sarcoplasmic reticulum. Excessive activation of ATG7-mediated autophagy also induces severe muscle loss214. VSMC-specific Atg7-KO causes sarcoplasmic reticulum swelling and imbalanced Ca2+ homeostasis, leading to altered contractility215. In colon epithelial conditional Atg7-KO mice, experimental colitis deteriorated, with more bacterial intrusion into the colonic epithelium. Furthermore, the expression of antimicrobial or antiparasitic peptides and the secretion of colonic mucins were diminished in the conditional Atg7KO mice, leading to abnormal microflora and colitis216. Mice deficient for pancreatic ATG7 suffered earlier death caused by inflammation, fibrosis, increased apoptosis and necroptosis, and declining exocrine and endocrine functions217. Experiments in the drosophila eye revealed that both ATG7 and Hsp27 are involved in normal eye development. Overexpression of ATG7 could rescue Hsp27-deficient phenotypes; however, overexpression of Hsp27 could not rescue ATG7-deficient phenotypes218. ATG7 also participates in liver pathology and the adipose-liver system. Adipocyte-specific loss of Atg7 enhances high-fat diet (HFD)-induced inguinal white adipose tissue hypertrophy, which downregulates serum-free fatty acid levels and relieves HFD-induced steatosis, liver inflammation, and fibrosis through adipose-liver crosstalk219. In certain diseases (e.g., AKI), activating ATG7-mediated autophagy might alleviate the symptoms. Understanding the various roles of ATG7 in different tissues could shed new light on targeting ATG7 to modulate diverse tissue dysfunctions.
ATG7 is regulated at DNA, mRNA, and protein levels, and is closely associated with transcription regulation, cell fate, energy metabolism, developmental regulation and aging diseases.
Multiple genetic and transcriptional mechanisms regulate the autophagy-dependent functions of ATG7. Transcription factors, transcriptional regulatory factors as well as miRNA, circRNA, lncRNA, and RBPs regulate Atg7 mRNA expression. Moreover, various post-translational modifications regulate ATG7 protein function. Although multiple regulatory mechanisms have been defined for the autophagy-dependent functions of ATG7, how the autophagy-independent functions of ATG7 are regulated remains unclear. Because ATG7 might be regulated differently when performing autophagy-dependent and autophagy-independent functions, it is important to determine how ATG7 switches between its autophagy-dependent and autophagy-independent roles.
DNA methylation can control genetic expression without altering DNA sequence by changing chromatin structure, DNA conformation, DNA stability, and DNA-protein interactions. Until recently, little was known about the DNA methylation of Atg7 and its functions. One study reported that Atg7 gene methylation can be affected by Legionella Infection, which causes a reduction in Atg7 mRNA57. The studies in monocytes and peripheral blood leukocytes showed that the methylation status and expression status of Atg7 might clue a novel epigenetic mechanism for CHD58. The epigenetic modifications of Atg7, including DNA methylation, require further study. Methylation is an important post-translational modification that adds methyl groups to amino acid residues in proteins, thereby altering protein structure and function. Methylation of a protein can regulate its stability, localization, and interactions, significantly affecting biological processes, including gene expression and cellular signaling. The methylation and other possible post-translational modifications of ATG7 protein are likely to have significant implications, and further research in this field is needed.
Along with the improvement of technologies and a comprehensive understanding of ATG7 regulatory mechanisms, it is anticipated that targeting ATG7 could benefit aging-related diseases. Future research should elucidate the specific molecular mechanisms underlying how ATG7 exerts its multiple functions and how these functions are related to aging diseases and corresponding therapies.
Data availability
All data are available online.
References
Mizushima, N. et al. A protein conjugation system essential for autophagy. Nature 395, 395–398 (1998).
Levy, J. M. M., Towers, C. G., and & Thorburn, A. Targeting autophagy in cancer. Nat. Rev. Cancer 17, 528–542 (2017).
Parzych, K. R. & Klionsky, D. J. An overview of autophagy: morphology, mechanism, and regulation. Antioxid. Redox Signal. 20, 460–473 (2014).
Levine, B. & Kroemer, G. Biological functions of autophagy genes: a disease perspective. Cell 176, 11–42 (2019).
Kaiser, S. E. et al. Noncanonical E2 recruitment by the autophagy E1 revealed by Atg7-Atg3 and Atg7-Atg10 structures. Nat. Struct. Mol. Biol. 19, 1242–1249 (2012).
Noda, N. N. et al. Structural basis of Atg8 activation by a homodimeric E1, Atg7. Mol. Cell 44, 462–475 (2011).
Kaiser, S. E. et al. Structures of Atg7-Atg3 and Atg7-Atg10 reveal noncanonical mechanisms of E2 recruitment by the autophagy E1. Autophagy 9, 778–780 (2013).
Klionsky, D. J. et al. Autophagy in major human diseases. EMBO J. 40, e108863 (2021).
Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018).
Komatsu, M. et al. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc. Natl Acad. Sci. USA 104, 14489–14494 (2007).
Mortensen, M. et al. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J. Exp. Med. 208, 455–467 (2011).
Zhang, Y. et al. Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. Proc. Natl Acad. Sci. USA 106, 19860–19865 (2009).
Teng, F. Y. et al. G-quadruplex DNA: a novel target for drug design. Cell Mol. Life Sci. 78, 6557–6583 (2021).
Lejault, P. et al. Regulation of autophagy by DNA G-quadruplexes. Autophagy 16, 2252–2259 (2020).
Moruno-Manchon, J. F. et al. Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons. Elife 9, e52283 (2020).
Zhang, P. et al. Functional variants of the ATG7 gene promoter in acute myocardial infarction. Mol. Genet. Genom. Med. 6, 1209–1219 (2018).
Portilla-Fernandez, E. et al. Dissecting the association of autophagy-related genes with cardiovascular diseases and intermediate vascular traits: a population-based approach. PLoS ONE 14, e0214137 (2019).
Zhou, J. et al. Evaluation of genetic variants in autophagy pathway genes as prognostic biomarkers for breast cancer. Gene 627, 549–555 (2017).
Dorsey, E. R. et al. The emerging evidence of the Parkinson pandemic. J. Parkinsons Dis. 8, S3–S8 (2018).
Chen, D. et al. Genetic analysis of the ATG7 gene promoter in sporadic Parkinson’s disease. Neurosci. Lett. 534, 193–198 (2013).
Zhao, X. et al. Associations of ATG7 rs1375206 polymorphism and elevated plasma ATG7 levels with late-onset sporadic Parkinson’s disease in a cohort of Han Chinese from southern China. Int. J. Neurosci. 130, 1206–1214 (2020).
Metzger, S. et al. Age at onset in Huntington’s disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7. Hum. Genet. 128, 453–459 (2010).
Metzger, S. et al. The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients. PLoS ONE 8, e68951 (2013).
Zhao, Y. et al. Anti-neoplastic activity of the cytosolic FoxO1 results from autophagic cell death. Autophagy 6, 988–990 (2010).
Zhao, Y. et al. Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat. Cell Biol. 12, 665–675 (2010).
He, W. et al. FOXO1, a potential therapeutic target, regulates autophagic flux, oxidative stress, mitochondrial dysfunction, and apoptosis in human cholangiocarcinoma QBC939 cells. Cell Physiol. Biochem. 45, 1506–1514 (2018).
Lu, J. et al. FOXO1 is a critical switch molecule for autophagy and apoptosis of sow endometrial epithelial cells caused by oxidative stress. Oxid. Med. Cell Longev. 2021, 1172273 (2021).
Sablon, A. et al. FOXO1 forkhead domain mutants in B-cell lymphoma lack transcriptional activity. Sci. Rep. 12, 1309 (2022).
Wang, S. et al. FoxO1-mediated autophagy is required for NK cell development and innate immunity. Nat. Commun. 7, 11023 (2016).
López-Soto, A. et al. Involvement of autophagy in NK cell development and function. Autophagy 13, 633–636 (2017).
Jiang, Y. et al. The role of FOXO1-mediated autophagy in the regulation of bone formation. Cell Cycle 22, 829–840 (2023).
Cai, J. et al. CK1α suppresses lung tumour growth by stabilizing PTEN and inducing autophagy. Nat. Cell Biol. 20, 465–478 (2018).
Zhao, L. et al. Autophagy deficiency leads to impaired antioxidant defense via p62-FOXO1/3 axis. Oxid. Med. Cell Longev. 2019, 2526314 (2019).
Kmiecik, S. W. & Mayer, M. P. Molecular mechanisms of heat shock factor 1 regulation. Trends Biochem. Sci. 47, 218–234 (2022).
Desai, S. et al. Heat shock factor 1 (HSF1) controls chemoresistance and autophagy through transcriptional regulation of autophagy-related protein 7 (ATG7). J. Biol. Chem. 288, 9165–9176 (2013).
Li, W. et al. MicroRNA-217 aggravates breast cancer through activation of NF1-mediated HSF1/ATG7 axis and c-Jun/ATF3/MMP13 axis. Hum. Cell 36, 377–392 (2022).
Luo, T. et al. PSMD10/gankyrin induces autophagy to promote tumor progression through cytoplasmic interaction with ATG7 and nuclear transactivation of ATG7 expression. Autophagy 12, 1355–1371 (2016).
Zheng, T. et al. Long noncoding RNA NBAT1 inhibits autophagy via suppression of ATG7 in non-small cell lung cancer. Am. J. Cancer Res. 8, 1801–1811 (2018).
Xu, Y. et al. Tgf-β1 induces autophagy and promotes apoptosis in renal tubular epithelial cells. Int. J. Mol. Med. 29, 781–790 (2012).
Guo, Y. et al. TGF-β/YB-1/Atg7 axis promotes the proliferation of hepatic progenitor cells and liver fibrogenesis. Biochim. Biophys. Acta Mol. Basis Dis. 1868, 166290 (2022).
Livingston, M. J. et al. Autophagy activates EGR1 via MAPK/ERK to induce FGF2 in renal tubular cells for fibroblast activation and fibrosis during maladaptive kidney repair. Autophagy 1–22 (2023). Online ahead of print.
Zhang, H. et al. Autophagy protects against vocal fold injury-induced fibrosis. J. Neurophysiol. 130, 1457–1463 (2023).
Han, S. et al. Omega-3 fatty acids attenuate renal fibrosis via AMPK-mediated autophagy flux activation. Biomedicines 11, 2553 (2023).
Wang, Y. et al. Preliminary study on the effect and molecular mechanism of tetrandrine in alleviating pulmonary inflammation and fibrosis induced by silicon dioxide. Toxics 11, 765 (2023).
Chen, X. et al. Autophagy gene Atg7 regulates the development of radiation-induced skin injury and fibrosis of skin. Ski. Res. Technol. 29, e13337 (2023).
Huang, Z. et al. Inhibition of IL-6/JAK/STAT3 pathway rescues denervation-induced skeletal muscle atrophy. Ann. Transl. Med. 8, 1681 (2020).
Maycotte, P. et al. STAT3-mediated autophagy dependence identifies subtypes of breast cancer where autophagy inhibition can be efficacious. Cancer Res. 74, 2579–2590 (2014).
Wan, Q. et al. Aspirin alleviates denervation-induced muscle atrophy via regulating the Sirt1/PGC-1α axis and STAT3 signaling. Ann. Transl. Med. 8, 1524 (2020).
An, Q. et al. Enhanced neutrophil autophagy and increased concentrations of IL-6, IL-8, IL-10 and MCP-1 in rheumatoid arthritis. Int. Immunopharmacol. 65, 119–128 (2018).
Luo, M. X. et al. Autophagy mediates HBx-induced nuclear factor-κB activation and release of IL-6, IL-8, and CXCL2 in hepatocytes. J. Cell Physiol. 230, 2382–2389 (2015).
Wang, S. et al. Intracellular alpha-fetoprotein interferes with all-trans retinoic acid induced ATG7 expression and autophagy in hepatocellular carcinoma cells. Sci. Rep. 11, 2146 (2021).
Zhao, Y. et al. CD13 induces autophagy to promote hepatocellular carcinoma cell chemoresistance through the P38/Hsp27/CREB/ATG7 pathway. J. Pharm. Exp. Ther. 374, 512–520 (2020).
Frangež, Ž. et al. ATG5 and ATG7 expression levels are reduced in cutaneous melanoma and regulated by NRF1. Front. Oncol. 11, 721624 (2021).
Li, S. et al. Autophagy attenuates compression-induced apoptosis of human nucleus pulposus cells via MEK/ERK/NRF1/Atg7 signaling pathways during intervertebral disc degeneration. Exp. Cell Res. 370, 87–97 (2018).
Niu, Y. et al. EVI1 induces autophagy to promote drug resistance via regulation of ATG7 expression in leukemia cells. Carcinogenesis 41, 961–971 (2020).
Moore, L. D., Le, T. & Fan, G. DNA methylation and its basic function. Neuropsychopharmacology 38, 23–38 (2013).
Abd, E. L. et al. Methylomic changes of autophagy-related genes by legionella effector Lpg2936 in infected macrophages. Front. Cell Dev. Biol. 7, 390 (2019).
Zhang, X. et al. Identification of DNA methylation-regulated genes as potential biomarkers for coronary heart disease via machine learning in the Framingham Heart Study. Clin. Epigenet. 14, 122 (2022).
Ghemrawi, R. et al. DNA and protein methyltransferases inhibition by adenosine dialdehyde reduces the proliferation and migration of breast and lung cancer cells by downregulating autophagy. PLoS ONE 18, e0288791 (2023).
Zhu, W. et al. Epigenetic alternations of microRNAs and DNA methylation contribute to gestational diabetes mellitus. J. Cell Mol. Med. 24, 13899–13912 (2020).
Zhang, S. Mechanism of N(6)-methyladenosine modification and its emerging role in cancer. Pharm. Ther. 189, 173–183 (2018).
Wang, X. et al. m(6)A mRNA methylation controls autophagy and adipogenesis by targeting Atg5 and Atg7. Autophagy 16, 1221–1235 (2020).
Chen, X. et al. METTL3-mediated m(6)A modification of ATG7 regulates autophagy-GATA4 axis to promote cellular senescence and osteoarthritis progression. Ann. Rheum. Dis. 81, 87–99 (2022).
Liu, S. et al. The mechanism of m(6)A methyltransferase METTL3-mediated autophagy in reversing gefitinib resistance in NSCLC cells by β-elemene. Cell Death Dis. 11, 969 (2020).
Lai, X. et al. Dysregulation of LINC00470 and METTL3 promotes chemoresistance and suppresses autophagy of chronic myelocytic leukaemia cells. J. Cell Mol. Med. 25, 4248–4259 (2021).
Chen, Q. et al. Hesperidin inhibits methylation and autophagy in LPS and high glucose-induced human villous trophoblasts. Biochem. Biophys. Res. Commun. 671, 278–285 (2023).
Diener, C., Keller, A. & Meese, E. Emerging concepts of miRNA therapeutics: from cells to clinic. Trends Genet. 38, 613–626 (2022).
Tan, L. et al. ETS2 promotes cardiomyocyte apoptosis and autophagy in heart failure by regulating lncRNA TUG1/miR-129-5p/ATG7 axis. FASEB J. 37, e22937 (2023).
Lv, X. W. et al. 6-Gingerol relieves myocardial ischaemia/reperfusion injury by regulating lncRNA H19/miR-143/ATG7 signaling axis-mediated autophagy. Lab. Invest. 101, 865–877 (2021).
Mo, Y. et al. LncRNA CHRF aggravates myocardial ischemia/reperfusion injury by enhancing autophagy via modulation of the miR-182-5p/ATG7 pathway. J. Biochem. Mol. Toxicol. 35, e22709 (2021).
Qiu, Z. et al. CircHIPK3 regulates the autophagy and apoptosis of hypoxia/reoxygenation-stimulated cardiomyocytes via the miR-20b-5p/ATG7 axis. Cell Death Discov. 7, 64 (2021).
Zhang, J. et al. miR-27a-5p attenuates hypoxia-induced rat cardiomyocyte injury by inhibiting Atg7. Int. J. Mol. Sci. 20, 2418 (2019).
Wang, F. et al. Hypoxia/reoxygenation-induced upregulation of miRNA-542-5p aggravated cardiomyocyte injury by repressing autophagy. Hum. Cell 34, 349–359 (2021).
Liu, J. et al. miR-93-5p-containing exosomes treatment attenuates acute myocardial infarction-induced myocardial damage. Mol. Ther. Nucleic Acids 11, 103–115 (2018).
Wang, K. et al. APF lncRNA regulates autophagy and myocardial infarction by targeting miR-188-3p. Nat. Commun. 6, 6779 (2015).
Song, Z. et al. LncRNA RASSF8-AS1 knockdown displayed antiproliferative and proapoptotic effects through miR-188-3p/ATG7 pathway in ox-LDL-treated vascular smooth muscle cells. Ann. Transl. Med. 11, 143 (2023).
Li, F. et al. circPAN3 exerts a profibrotic role via sponging miR-221 through FoxO3/ATG7-activated autophagy in a rat model of myocardial infarction. Life Sci. 257, 118015 (2020).
Ma, W. et al. By targeting Atg7 microRNA-143 mediates oxidative stress-induced autophagy of c-Kit(+) mouse cardiac progenitor cells. EBioMedicine 32, 182–191 (2018).
Yang, J. et al. LncRNA 0003250 accelerates heart autophagy and binds to miR-17-5p as a competitive endogenous RNA in chicken induced by selenium deficiency. J. Cell Physiol. 236, 157–177 (2021).
Wang, C. et al. MiR-7-5p suppresses invasion via downregulation of the autophagy-related gene ATG7 and increases chemoresistance to cisplatin in BCa. Bioengineered 13, 7328–7339 (2022).
Pan, X. et al. Knockdown of TRIM65 inhibits autophagy and cisplatin resistance in A549/DDP cells by regulating miR-138-5p/ATG7. Cell Death Dis. 10, 429 (2019).
Wang, W. et al. miR-4486 reverses cisplatin-resistance of colon cancer cells via targeting ATG7 to inhibiting autophagy. Exp. Ther. Med. 22, 1465 (2021).
Wang, H. et al. Long non-coding RNA NNT-AS1 contributes to cisplatin resistance via miR-1236-3p/ATG7 axis in lung cancer cells. Onco Targets Ther. 13, 3641–3652 (2020).
Zeng, Y. et al. MIR137 regulates starvation-induced autophagy by targeting ATG7. J. Mol. Neurosci. 56, 815–821 (2015).
Pan, R. & Zhou, H. Exosomal transfer of lncRNA H19 promotes erlotinib resistance in non-small cell lung cancer via miR-615-3p/ATG7 axis. Cancer Manag. Res. 12, 4283–4297 (2020).
Huang, F. X. et al. LncRNA BLACAT1 is involved in chemoresistance of non‑small cell lung cancer cells by regulating autophagy. Int. J. Oncol. 54, 339–347 (2019).
Ma, L. et al. Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7. Cell Death Dis. 11, 169 (2020).
Wei, R. et al. microRNA-375 inhibits colorectal cancer cells proliferation by downregulating JAK2/STAT3 and MAP3K8/ERK signaling pathways. Oncotarget 8, 16633–16641 (2017).
Chang, Y. et al. miR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions. Gastroenterology 143, 177–87.e8 (2012).
Ou, Y., He, J. & Liu, Y. MiR-490-3p inhibits autophagy via targeting ATG7 in hepatocellular carcinoma. IUBMB Life 70, 468–478 (2018).
Gao, A. M. et al. Apigenin sensitizes hepatocellular carcinoma cells to doxorubic through regulating miR-520b/ATG7 axis. Chem. Biol. Interact. 280, 45–50 (2018).
Guo, J. et al. LncRNA CCAT1 promotes autophagy via regulating ATG7 by sponging miR-181 in hepatocellular carcinoma. J. Cell Biochem. 120, 17975–17983 (2019).
Wang, X. et al. LncRNA DANCR promotes ATG7 expression to accelerate hepatocellular carcinoma cell proliferation and autophagy by sponging miR-222-3p. Eur. Rev. Med. Pharm. Sci. 24, 8778–8787 (2020).
Tang, C. et al. lncRNA TINCR regulates proliferation and invasion of hepatocellular carcinoma cells by regulating the miR-375/ATG7 axis. J. Oncol. 2022, 8132403 (2022).
Guo, J. et al. Downregulation of miR-17-92a cluster promotes autophagy induction in response to celastrol treatment in prostate cancer cells. Biochem. Biophys. Res. Commun. 478, 804–810 (2016).
Comincini, S. et al. microRNA-17 regulates the expression of ATG7 and modulates the autophagy process, improving the sensitivity to temozolomide and low-dose ionizing radiation treatments in human glioblastoma cells. Cancer Biol. Ther. 14, 574–586 (2013).
Chen, J. et al. Low-dose endothelial-monocyte-activating polypeptide-II induced autophagy by down-regulating miR-20a in U-87 and U-251 glioma cells. Front. Cell Neurosci. 10, 128 (2016).
Wang, M. et al. Purple sweet potato delphinidin-3-rutin represses glioma proliferation by inducing miR-20b-5p/Atg7-dependent cytostatic autophagy. Mol. Ther. Oncolytics 26, 314–329 (2022).
Ma, Y. et al. PVT1 affects growth of glioma microvascular endothelial cells by negatively regulating miR-186. Tumour Biol. 39, 1010428317694326 (2017).
Ma, Y. et al. Biphasic regulation of autophagy by miR-96 in prostate cancer cells under hypoxia. Oncotarget 5, 9169–9182 (2014).
Wu, Z. B. et al. MicroRNA expression profile of bromocriptine-resistant prolactinomas. Mol. Cell Endocrinol. 395, 10–18 (2014).
Wu, Z. et al. MicroRNA-93 mediates cabergoline-resistance by targeting ATG7 in prolactinoma. J. Endocrinol. 240, 1–13 (2019).
Yu, Y. et al. MiR-20a-5p suppresses tumor proliferation by targeting autophagy-related gene 7 in neuroblastoma. Cancer Cell Int. 18, 5 (2018).
Hao, H. et al. miR-106a suppresses tumor cells death in colorectal cancer through targeting ATG7. Med. Mol. Morphol. 50, 76–85 (2017).
Ju, S. et al. The effect and mechanism of miR-210 in down-regulating the autophagy of lung cancer cells. Pathol. Res. Pr. 215, 453–458 (2019).
Zhou, Q. et al. ATG7-mediated autophagy involves in miR-138-5p regulated self-renewal and invasion of lung cancer stem-like cells derived from A549 cells. Anticancer Drugs 32, 376–385 (2021).
Zhu, J. et al. ATG7 promotes bladder cancer invasion via autophagy-mediated increased ARHGDIB mRNA stability. Adv. Sci. 6, 1801927 (2019).
Li, J. J. et al. Long non-coding RNA UCA1 promotes autophagy by targeting miR-96-5p in acute myeloid leukaemia. Clin. Exp. Pharm. Physiol. 47, 877–885 (2020).
Zhang, J. et al. MicroRNA‑154 functions as a tumor suppressor in bladder cancer by directly targeting ATG7. Oncol. Rep. 41, 819–828 (2019).
Wang, Q. et al. Hsa_circ_0092276 promotes doxorubicin resistance in breast cancer cells by regulating autophagy via miR-348/ATG7 axis. Transl. Oncol. 14, 101045 (2021).
Yong, M. et al. Circ-EEF2 facilitated autophagy via interaction with mir-6881-3p and ANXA2 in EOC. Am. J. Cancer Res. 10, 3737–3751 (2020).
Gui, F. et al. Mechanism of LncHOTAIR regulating proliferation, apoptosis, and autophagy of lymphoma cells through hsa-miR-6511b-5p/ATG7 axis. Evid. Based Complement. Altern. Med. 2022, 2166605 (2022).
He, Z. et al. Autophagy-associated circRNA circATG7 facilitates autophagy and promotes pancreatic cancer progression. Cell Death Dis. 13, 233 (2022).
Liu, Z. et al. Autophagy-related gene 7 deficiency caused by miR-154-5p overexpression suppresses the cell viability and tumorigenesis of retinoblastoma by increasing cell apoptosis. Ann. Transl. Med. 8, 1451 (2020).
Qin, Y. et al. ATF2-induced lncRNA GAS8-AS1 promotes autophagy of thyroid cancer cells by targeting the miR-187-3p/ATG5 and miR-1343-3p/ATG7 axes. Mol. Ther. Nucleic Acids 22, 584–600 (2020).
Wang, S. et al. miR‑654‑5p inhibits autophagy by targeting ATG7 via mTOR signaling in intervertebral disc degeneration. Mol. Med. Rep. 23, 444 (2021).
Chen, J. et al. Effect of miR-202-5p-mediated ATG7 on autophagy and apoptosis of degenerative nucleus pulposus cells. Eur. Rev. Med. Pharm. Sci. 24, 517–525 (2020).
Hai, B. et al. Melatonin benefits to the growth of human annulus fibrosus cells through inhibiting miR-106a-5p/ATG7 signaling pathway. Clin. Inter. Aging 14, 621–630 (2019).
Zhao, L. et al. Association of miR-192-5p with atherosclerosis and its effect on proliferation and migration of vascular smooth muscle cells. Mol. Biotechnol. 63, 1244–1251 (2021).
Qin, Q. W. et al. ZNF295-AS1 inhibits autophagy via the ZNF295-AS1/miR-508-5p/ATG7 axis in AS. Eur. Rev. Med. Pharm. Sci. 24, 7024–7032 (2020).
Wu, Z. et al. Sevoflurane up-regulates miR-7a to protect against ischemic brain injury in rats by down-regulating ATG7 and reducing neuronal autophagy. Brain Res. Bull. 188, 214–222 (2022).
Li, T. H. et al. Long non-coding RNA MEG3 regulates autophagy after cerebral ischemia/reperfusion injury. Neural Regen. Res. 17, 824–831 (2022).
Cao, Y. et al. LncRNA SNHG3 promotes autophagy-induced neuronal cell apoptosis by acting as a ceRNA for miR-485 to up-regulate ATG7 expression. Metab. Brain Dis. 35, 1361–1369 (2020).
Pei, X. et al. Astrocyte-derived exosomes transfer miR-190b to inhibit oxygen and glucose deprivation-induced autophagy and neuronal apoptosis. Cell Cycle 19, 906–917 (2020).
Guo, L. et al. microRNA-20a inhibits autophagic process by targeting ATG7 and ATG16L1 and favors mycobacterial survival in macrophage cells. Front. Cell Infect. Microbiol. 6, 134 (2016).
Liu, K. et al. MicroRNA-106a inhibits autophagy process and antimicrobial responses by targeting ULK1, ATG7, and ATG16L1 during mycobacterial infection. Front. Immunol. 11, 610021 (2020).
Yu, Y., Men, S. & Zhang, Y. miR-20a-5p ameliorates ovalbumin (OVA)-induced mouse model of allergic asthma through targeting ATG7-regulated cell death, fibrosis and inflammation. Int. Immunopharmacol. 95, 107342 (2021).
Huang, J. et al. MicroRNA-590-3p inhibits T helper 17 cells and ameliorates inflammation in lupus mice. Immunology 165, 260–273 (2022).
Yu, J. et al. MiR-146a-5p accelerates sepsis through dendritic cell activation and glycolysis via targeting ATG7. J. Biochem. Mol. Toxicol. 36, e23151 (2022).
Liu, Y. et al. ATG7 promotes autophagy in sepsis‑induced acute kidney injury and is inhibited by miR‑526b. Mol. Med. Rep. 21, 2193–2201 (2020).
Zhang, S. et al. Phototrophy and starvation-based induction of autophagy upon removal of Gcn5-catalyzed acetylation of Atg7 in Magnaporthe oryzae. Autophagy 13, 1318–1330 (2017).
Zhou, W. et al. Triamcinolone acetonide combined with 5-fluorouracil suppresses urethral scar fibroblasts autophagy and fibrosis by increasing miR-192-5p expression. Am. J. Transl. Res. 13, 5956–5968 (2021).
Liu, T. et al. Down-regulation of miR-204 attenuates endothelial-mesenchymal transition by enhancing autophagy in hypoxia-induced pulmonary hypertension. Eur. J. Pharm. 863, 172673 (2019).
Tang, B. et al. Long noncoding RNA HOTAIR regulates autophagy via the miR-20b-5p/ATG7 axis in hepatic ischemia/reperfusion injury. Gene 686, 56–62 (2019).
Cao, M. et al. Long non-coding RNA WAC antisense RNA 1 mediates hepatitis B virus replication in vitro by reinforcing miR-192-5p/ATG7-induced autophagy. Eur. J. Histochem. 66, 3438 (2022).
Zhou, W. et al. circRNA expression profiling of colon tissue from mesalazine-treated mouse of inflammatory bowel disease reveals an important circRNA-miRNA-mRNA pathway. Aging 13, 10187–10207 (2021).
Tian, D. et al. Circ-ADAM9 targeting PTEN and ATG7 promotes autophagy and apoptosis of diabetic endothelial progenitor cells by sponging mir-20a-5p. Cell Death Dis. 11, 526 (2020).
Geng, X. et al. Tumor cell derived Lnc-FSD2-31:1 contributes to cancer-associated fibroblasts activation in pancreatic ductal adenocarcinoma progression through extracellular vesicles cargo MiR-4736. Adv. Sci. 10, e2203324 (2023).
Wang, Y. et al. Hsa_circ_0004058 inhibits apoptosis of SRA01/04 cells by promoting autophagy via miR-186/ATG7 axis. Exp. Eye Res. 211, 108721 (2021).
Herman, A. B., Tsitsipatis, D. & Gorospe, M. Integrated lncRNA function upon genomic and epigenomic regulation. Mol. Cell 82, 2252–2266 (2022).
He, C. et al. Long non-coding RNA SNHG8 promotes autophagy as a ceRNA to upregulate ATG7 by sponging microRNA-588 in colorectal cancer. Oncol. Lett. 22, 577 (2021).
Chen, S. et al. The lncRNA HULC functions as an oncogene by targeting ATG7 and ITGB1 in epithelial ovarian carcinoma. Cell Death Dis. 8, e3118 (2017).
Xue, C. et al. The functional roles of the circRNA/Wnt axis in cancer. Mol. Cancer 21, 108 (2022).
Dai, W., Liu, H. & Zhang, P. Hsa_circ_0006948 regulates the proliferation, migration and invasion in osteosarcoma by regulation of the expression of miR-490-3p target ATG7. Zhonghua Zhong Liu Za Zhi 43, 457–465 (2021).
Wei, M. Y., Lv, R. R. & Teng, Z. Circular RNA circHIPK3 as a novel circRNA regulator of autophagy and endothelial cell dysfunction in atherosclerosis. Eur. Rev. Med. Pharm. Sci. 24, 12849–12858 (2020).
Palanisamy, K. et al. RNA-binding protein, human antigen R regulates hypoxia-induced autophagy by targeting ATG7/ATG16L1 expressions and autophagosome formation. J. Cell Physiol. 234, 7448–7458 (2019).
Shao, Z. et al. RNA-binding protein HuR suppresses senescence through Atg7 mediated autophagy activation in diabetic intervertebral disc degeneration. Cell Prolif. 54, e12975 (2021).
Si, X. et al. LncRNA DDX11-AS1 promotes chemoresistance through LIN28A-mediated ATG12 mRNA stabilization in breast cancer. Pharmacology 108, 61–73 (2023).
Park, S. M. et al. U2AF35(S34F) promotes transformation by directing aberrant ATG7 pre-mRNA 3’ end formation. Mol. Cell 62, 479–490 (2016).
Lee, I. H. & Finkel, T. Regulation of autophagy by the p300 acetyltransferase. J. Biol. Chem. 284, 6322–6328 (2009).
Sebti, S. et al. BAT3 modulates p300-dependent acetylation of p53 and autophagy-related protein 7 (ATG7) during autophagy. Proc. Natl Acad. Sci. USA 111, 4115–4120 (2014).
Sebti, S. et al. BAG6/BAT3 modulates autophagy by affecting EP300/p300 intracellular localization. Autophagy 10, 1341–1342 (2014).
Wang, J. et al. HLA-DMB restricts human T-cell leukemia virus type-1 (HTLV-1) protein expression via regulation of ATG7 acetylation. Sci. Rep. 7, 14416 (2017).
Lee, I. H. et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc. Natl Acad. Sci. USA 105, 3374–3379 (2008).
Liao, F. X. et al. The new role of Sirtuin1 in human osteoarthritis chondrocytes by regulating autophagy. Cartilage 13, 1237s–1248s (2021).
Sacitharan, P. K., Bou-Gharios, G. & Edwards, J. R. SIRT1 directly activates autophagy in human chondrocytes. Cell Death Discov. 6, 41 (2020).
Wu, B. et al. Aldehyde dehydrogenase 2 activation in aged heart improves the autophagy by reducing the carbonyl modification on SIRT1. Oncotarget 7, 2175–2188 (2016).
Wang, Y. et al. Role of p53/miR-155-5p/sirt1 loop in renal tubular injury of diabetic kidney disease. J. Transl. Med. 16, 146 (2018).
Cao, L. et al. Role of K63-linked ubiquitination in cancer. Cell Death Discov. 8, 410 (2022).
Wang, J. et al. TRIM7/RNF90 promotes autophagy via regulation of ATG7 ubiquitination during L. monocytogenes infection. Autophagy 19, 1844–1862 (2023).
Li, L. et al. ROS and autophagy: interactions and molecular regulatory mechanisms. Cell Mol. Neurobiol. 35, 615–621 (2015).
Liu, J. et al. ATM-CHK2-TRIM32 axis regulates ATG7 ubiquitination to initiate autophagy under oxidative stress. Cell Rep. 42, 113402 (2023).
Tanida, I. et al. GATE-16 and GABARAP are authentic modifiers mediated by Apg7 and Apg3. Biochem. Biophys. Res. Commun. 300, 637–644 (2003).
Martens, S. & Fracchiolla, D. Activation and targeting of ATG8 protein lipidation. Cell Discov. 6, 23 (2020).
Wu, H. et al. Caspases: a molecular switch node in the crosstalk between autophagy and apoptosis. Int. J. Biol. Sci. 10, 1072–1083 (2014).
Li, M. et al. Autophagy-related 7 modulates tumor progression in triple-negative breast cancer. Lab. Invest. 99, 1266–1274 (2019).
Wang, Y. et al. Regulation of proliferation and apoptosis of aging periodontal ligament cells by autophagy-related gene 7. Mol. Biol. Rep. 50, 6361–6372 (2023).
Xu, X. et al. Atg7 mediates renal tubular cell apoptosis in vancomycin nephrotoxicity through activation of PKC-δ. FASEB J. 33, 4513–4524 (2019).
Niture, S. et al. TNFAIP8 regulates autophagy, cell steatosis, and promotes hepatocellular carcinoma cell proliferation. Cell Death Dis. 11, 178 (2020).
Wei, Y. et al. ERβ promotes Aβ degradation via the modulation of autophagy. Cell Death Dis. 10, 565 (2019).
Cao, Y. et al. Hierarchal autophagic divergence of hematopoietic system. J. Biol. Chem. 290, 23050–23063 (2015).
Ge, C. et al. Autophagy-deficient mice are more susceptible to engrafted leukemogenesis. Blood Cells Mol. Dis. 77, 129–136 (2019).
Watson, A. S. et al. Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia. Cell Death Discov. 1, 15008 (2015).
Cao, Y. et al. Autophagy regulates the cell cycle of murine HSPCs in a nutrient-dependent manner. Exp. Hematol. 43, 229–242 (2015).
Yuan, Y. et al. Deterioration of hematopoietic autophagy is linked to osteoporosis. Aging Cell 19, e13114 (2020).
Cao, Y. et al. Loss of autophagy leads to failure in megakaryopoiesis, megakaryocyte differentiation, and thrombopoiesis in mice. Exp. Hematol. 43, 488–494 (2015).
Fang, Y. et al. Blood autophagy defect causes accelerated non-hematopoietic organ aging. Aging 11, 4910–4922 (2019).
Maity, J. et al. Ferutinin induces osteoblast differentiation of DPSCs via induction of KLF2 and autophagy/mitophagy. Cell Death Dis. 13, 452 (2022).
Ezzat, S. et al. Autophagy in osteoporosis: relation to oxidative stress. J. Cell Biochem. 120, 2560–2568 (2019).
Fu, L. et al. Glucocorticoids enhanced osteoclast autophagy through the PI3K/Akt/mTOR signaling pathway. Calcif. Tissue Int. 107, 60–71 (2020).
Mahanty, S. & Setty, S. R. G. Epidermal lamellar body biogenesis: insight into the roles of Golgi and lysosomes. Front. Cell Dev. Biol. 9, 701950 (2021).
Morishita, H. et al. Autophagy is required for maturation of surfactant-containing lamellar bodies in the lung and swim bladder. Cell Rep. 33, 108477 (2020).
Li, X. et al. The role of autophagy in lamellar body formation and surfactant production in type 2 alveolar epithelial cells. Int. J. Biol. Sci. 18, 1107–1119 (2022).
Yeganeh, B. et al. Autophagy is required for lung development and morphogenesis. J. Clin. Invest. 129, 2904–2919 (2019).
Wang, G. et al. Atg7-mediated autophagy is involved in the neural crest cell generation in chick embryo. Mol. Neurobiol. 55, 3523–3536 (2018).
Pan, X. et al. Accumulation of prelamin A induces premature aging through mTOR overactivation. FASEB J. 34, 7905–7914 (2020).
Liu, H. et al. Endothelial depletion of Atg7 triggers astrocyte-microvascular disassociation at blood-brain barrier. J. Cell Biol. 222, e202103098 (2023).
Torisu, T. et al. Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor. Nat. Med. 19, 1281–1287 (2013).
Lu, W. H. et al. Proper autophagy is indispensable for angiogenesis during chick embryo development. Cell Cycle 15, 1742–1754 (2016).
Li, S. et al. Autophagy is involved in ethanol-induced cardia bifida during chick cardiogenesis. Cell Cycle 14, 3306–3317 (2015).
Wang, G. et al. Autophagy is involved in high glucose-induced heart tube malformation. Cell Cycle 14, 772–783 (2015).
Pastushenko, I. & Blanpain, C. EMT transition states during tumor progression and metastasis. Trends Cell Biol. 29, 212–226 (2019).
Feng, H. et al. Autophagy resists EMT process to maintain retinal pigment epithelium homeostasis. Int. J. Biol. Sci. 15, 507–521 (2019).
Lu, W. H. et al. Autophagy functions on EMT in gastrulation of avian embryo. Cell Cycle 13, 2752–2764 (2014).
Wu, J. J. et al. Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy. Aging 1, 425–437 (2009).
Chen, S. et al. Betaine attenuates age-related suppression in autophagy via Mettl21c/p97/VCP axis to delay muscle loss. J. Nutr. Biochem. 125, 109555 (2023).
Bhuiyan, M. S. et al. Enhanced autophagy ameliorates cardiac proteinopathy. J. Clin. Invest. 123, 5284–5297 (2013).
Seo, S. U. et al. Itch and autophagy-mediated NF-κB activation contributes to inhibition of cathepsin D-induced sensitizing effect on anticancer drugs. Cell Death Dis. 13, 552 (2022).
Agupitan, A. D. et al. P53: a guardian of immunity becomes its saboteur through mutation. Int. J. Mol. Sci. 21, 3452 (2020).
Liebl, M. C. & Hofmann, T. G. The role of p53 signaling in colorectal cancer. Cancers 13, 2125 (2021).
Feng, Z. et al. The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl Acad. Sci. USA 102, 8204–8209 (2005).
Yang, Y. et al. Autophagy promotes mammalian survival by suppressing oxidative stress and p53. Genes Dev. 34, 688–700 (2020).
Lee, I. H. et al. Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress. Science 336, 225–228 (2012).
Yamaguchi, T. et al. The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function. Sci. Signal. 11, eaan3638 (2018).
Nohl, E. K. et al. Improved analysis of prostate cancer: VIM3, ATG7 and P53 form a complex and activate miRNA 371a-3p. Anticancer Res. 43, 2407–2416 (2023).
Vincent, M. Cancer: a de-repression of a default survival program common to all cells?: a life-history perspective on the nature of cancer. Bioessays 34, 72–82 (2012).
Feng, Y. et al. Atg7 inhibits Warburg effect by suppressing PKM2 phosphorylation resulting reduced epithelial-mesenchymal transition. Int. J. Biol. Sci. 14, 775–783 (2018).
Zhuang, S. F. et al. Atg7 regulates brain angiogenesis via NF-κB-dependent IL-6 production. Int. J. Mol. Sci. 18, 968 (2017).
Wang, H. J. et al. Endothelial Atg7 deficiency ameliorates acute cerebral injury induced by ischemia/reperfusion. Front. Neurol. 9, 998 (2018).
Xue, J. F. et al. Inhibition of PI3K/AKT/mTOR signaling pathway promotes autophagy of articular chondrocytes and attenuates inflammatory response in rats with osteoarthritis. Biomed. Pharmacother. 89, 1252–1261 (2017).
Mo, H., Yang, S. & Chen, A. M. Inhibition of GAB2 expression has a protective effect on osteoarthritis: an in vitro and in vivo study. Biochem. Biophys. Res. Commun. 626, 229–235 (2022).
Fang, Y. et al. Loss of Atg7 causes chaotic nucleosome assembly of mouse bone marrow CD11b(+)Ly6G(-) myeloid cells. Aging 12, 25673–25683 (2020).
Huang, H. et al. Reciprocal network between cancer stem-like cells and macrophages facilitates the progression and androgen deprivation therapy resistance of prostate cancer. Clin. Cancer Res. 24, 4612–4626 (2018).
Masiero, E. et al. Autophagy is required to maintain muscle mass. Cell Metab. 10, 507–515 (2009).
Michiels, C. F. et al. Defective autophagy in vascular smooth muscle cells alters contractility and Ca2+ homeostasis in mice. Am. J. Physiol. Heart Circ. Physiol. 308, H557–H567 (2015).
Tsuboi, K. et al. Autophagy protects against colitis by the maintenance of normal gut microflora and secretion of mucus. J. Biol. Chem. 290, 20511–20526 (2015).
Zhou, X. et al. RIP3 attenuates the pancreatic damage induced by deletion of ATG7. Cell Death Dis. 8, e2918 (2017).
Chen, S. F. et al. Autophagy-related gene 7 is downstream of heat shock protein 27 in the regulation of eye morphology, polyglutamine toxicity, and lifespan in Drosophila. J. Biomed. Sci. 19, 52 (2012).
Sakane, S. et al. White adipose tissue autophagy and adipose-liver crosstalk exacerbate nonalcoholic fatty liver disease in mice. Cell Mol. Gastroenterol. Hepatol. 12, 1683–1699 (2021).
Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).
Liu, P. et al. Decreased autophagosome biogenesis, reduced NRF2, and enhanced ferroptotic cell death are underlying molecular mechanisms of non-alcoholic fatty liver disease. Redox Biol. 59, 102570 (2023).
Zhuang, Y. et al. Atg7 knockdown augments concanavalin A-induced acute hepatitis through an ROS-mediated p38/MAPK pathway. PLoS ONE 11, e0149754 (2016).
Livingston, M. J. et al. Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis. Autophagy 19, 256–277 (2023).
Jiang, M. et al. Autophagy in proximal tubules protects against acute kidney injury. Kidney Int. 82, 1271–1283 (2012).
Hernández-Gea, V. et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938–946 (2012).
Williams, P. A. et al. Intestinal epithelial autophagy is required for the regenerative benefit of calorie restriction. Am. J. Physiol. Gastrointest. Liver Physiol. 324, G354–G368 (2023).
Liu, H. et al. Intestinal epithelial cell autophagy deficiency suppresses inflammation-associated colon tumorigenesis. Mol. Ther. Nucleic Acids 28, 35–46 (2022).
Lévy, J. et al. Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth. Nat. Cell Biol. 17, 1062–1073 (2015).
Fukae, T. et al. Genetic ablation of p62/SQSTM1 demonstrates little effect on pancreatic β-cell function under autophagy deficiency. Biochem. Biophys. Res. Commun. 612, 99–104 (2022).
Chu, K. Y. et al. Short-term inhibition of autophagy benefits pancreatic β-cells by augmenting ether lipids and peroxisomal function, and by countering depletion of n-3 polyunsaturated fatty acids after fat-feeding. Mol. Metab. 40, 101023 (2020).
Wu, S. Y. et al. Secretory autophagy promotes Rab37-mediated exocytosis of tissue inhibitor of metalloproteinase 1. J. Biomed. Sci. 29, 103 (2022).
Zhao, Y. et al. Autophagy is induced by UVA and promotes removal of oxidized phospholipids and protein aggregates in epidermal keratinocytes. J. Invest. Dermatol. 133, 1629–1637 (2013).
Rossiter, H. et al. Epidermal keratinocytes form a functional skin barrier in the absence of Atg7 dependent autophagy. J. Dermatol. Sci. 71, 67–75 (2013).
Li, K. C. et al. Loss of Atg7 in endothelial cells enhanced cutaneous wound healing in a mouse model. J. Surg. Res. 249, 145–155 (2020).
Nilsson, P. et al. Aβ secretion and plaque formation depend on autophagy. Cell Rep. 5, 61–69 (2013).
Gomes, L. C., Di Benedetto, G. & Scorrano, L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat. Cell Biol. 13, 589–598 (2011).
Sung, H. K. et al. Autophagy deficiency exacerbates iron overload induced reactive oxygen species production and apoptotic cell death in skeletal muscle cells. Cell Death Dis. 14, 252 (2023).
De Munck, D. G. et al. Mouse aortic biomechanics are affected by short-term defective autophagy in vascular smooth muscle cells. J. Physiol. Sci. 72, 7 (2022).
He, H. Q. et al. AGEs-induced calcification and apoptosis in human vascular smooth muscle cells is reversed by inhibition of autophagy. Front. Pharm. 12, 692431 (2021).
Xing, Y., Song, L. & Zhang, Y. Autophagy is possibly involved in osteoblast responses to mechanical loadings. Curr. Issues Mol. Biol. 44, 3611–3620 (2022).
Riffelmacher, T. et al. Autophagy-dependent generation of free fatty acids is critical for normal neutrophil differentiation. Immunity 47, 466–480.e5 (2017).
Xu, F. et al. Autophagy promotes the repair of radiation-induced DNA damage in bone marrow hematopoietic cells via enhanced STAT3 signaling. Radiat. Res. 187, 382–396 (2017).
Zhu, J. et al. ATG7 overexpression is crucial for tumorigenic growth of bladder cancer in vitro and in vivo by targeting the ETS2/miRNA196b/FOXO1/p27 axis. Mol. Ther. Nucleic Acids 7, 299–313 (2017).
Acknowledgements
This work was supported by the key project of the National Natural Science Foundation (82030091), the key project of LiaoNing Science Foundation (2022JH6/100100037, 2022JH2/20200034, 2021JH2/10300023), the National Natural Science Foundation (82102740) and the Natural Science Foundation of Liaoning Province (2022-BS-144).
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Writing—original draft preparation: J.W.L., Y.T.X., L.Z.C., S.M.L., S.Y.Z., R.H.Y., Y.B.W., N.J.Z., Y.Y., X.W.W., W.D.G. and Z.W.; writing—review and editing: H.D.X., C.Z.X., X.Y.S. and L.C.
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Liu, J., Xiao, Y., Cao, L. et al. Insights on E1-like enzyme ATG7: functional regulation and relationships with aging-related diseases. Commun Biol 7, 382 (2024). https://doi.org/10.1038/s42003-024-06080-1
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DOI: https://doi.org/10.1038/s42003-024-06080-1
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