Featured
-
-
Article
| Open AccessNuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation
Zhen and colleagues show that nuclear cGAS represses L1 retrotransposition to stabilize the genome by enhancing the interaction between ORF2p and the E3 ligase TRIM41 upon DNA damage, which leads to the ubiquitination and degradation of ORF2p.
- Zhengyi Zhen
- , Yu Chen
- & Zhiyong Mao
-
Article
| Open AccessThe assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination
The role that cellular bioenergetics plays in the early stages of Alzheimer’s disease is poorly understood. Here the authors describe structures of key OXPHOS assembly proteins, providing insights into how these pathways are interlinked and regulated.
- Lindsay McGregor
- , Samira Acajjaoui
- & Montserrat Soler-Lopez
-
Article
| Open AccessStructure of the complete Saccharomyces cerevisiae Rpd3S-nucleosome complex
In this study, the authors present the cryogenic electron microscopy reconstruction of the Rpd3S complex engaged with a nucleosome. The corresponding model describes the interactions that facilitate histone deacetylation within gene bodies by the Rpd3S complex.
- Jonathan W. Markert
- , Seychelle M. Vos
- & Lucas Farnung
-
Article
| Open AccessCharacterization of nucleolar SUMO isopeptidases unveils a general p53-independent checkpoint of impaired ribosome biogenesis
Ribosome biogenesis is tightly coordinated with cell-cycle progression. By characterizing the SUMO isopeptidases SENP3/SENP5, Doenig et al. identify a long-sought p53-independent impaired ribosome checkpoint that converges on downregulation of CDK6.
- Judith Dönig
- , Hannah Mende
- & Stefan Müller
-
Article
| Open AccessAcetylation regulates the oligomerization state and activity of RNase J, the Helicobacter pylori major ribonuclease
Here the authors find that RNase J, the major ribonuclease of the gastric pathogen Helicobacter pylori is post-translationally modified by acetylation. They show that acetylation can control RNase J activity.
- Alejandro Tejada-Arranz
- , Aleksei Lulla
- & Hilde De Reuse
-
Article
| Open AccessCaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection
Here the authors show that the calcium-sensing kinase CaMKK2 phosphorylates STN1 in response to replication stress and elevated cytosolic calcium concentration to protect stalled replication forks from aberrant MRE11 degradation. Cancer-associated STN1 mutations abolish STN1 phosphorylation, resulting in fork instability.
- Rishi Kumar Jaiswal
- , Kai-Hang Lei
- & Weihang Chai
-
Article
| Open AccessBioE3 identifies specific substrates of ubiquitin E3 ligases
Here, the authors describe BioE3, a biotin-based method to discriminate direct substrates of ubiquitin E3 ligases of interest from mere interactors using proximity proteomics. BioE3 responds to chemical treatments, and works with RING- and HECT-type E3s, as well as ubiquitin-likes (e.g., SUMO).
- Orhi Barroso-Gomila
- , Laura Merino-Cacho
- & James D. Sutherland
-
Article
| Open AccessPTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling
TBK1 plays a central role in the antiviral innate response. Here the authors identify PTK2B as an interacting protein linked to TBK1 and STING oligomerisation and the activation of STING-TBK1 signaling.
- Yongfang Lin
- , Jing Yang
- & Qinmiao Sun
-
Article
| Open AccessSEPTIN2 suppresses an IFN-γ-independent, proinflammatory macrophage activation pathway
Interferon-gamma (IFN-γ) is an important but not exclusive proinflammatory mediator in macrophages. Here authors show that IFN-γ-independent macrophage autoactivation involves endoplasmic reticulum (ER) stress which in turn induces the GTP-binding protein Septin2 to limit inflammation via a negative feedback loop.
- Beibei Fu
- , Yan Xiong
- & Haibo Wu
-
Article
| Open AccessFunctional and structural diversity in deubiquitinases of the Chlamydia-like bacterium Simkania negevensis
Intracellular bacteria use deubiquitinase effectors to avoid being targeted for autophagic clearance. The authors show that the Chlamydia-like bacterium Simkania negevensis encodes an unusually broad range of these enzymes, including members that specifically target linear and K6-linked ubiquitin chains.
- Vanessa Boll
- , Thomas Hermanns
- & Kay Hofmann
-
Article
| Open AccessThe E3 ligase Riplet promotes RIG-I signaling independent of RIG-I oligomerization
Riplet conjugates K63-Ub chain to RIG-I in order to induce a robust antiviral response, but the mechanism of action remains unclear. Here, the authors show that Riplet recognizes RIG-I regardless of its RNA-bound status and promotes RIG-I signaling independent of RIG-I oligomerization.
- Wenshuai Wang
- , Benjamin Götte
- & Anna Marie Pyle
-
Article
| Open AccessSARS-CoV-2 hijacks a cell damage response, which induces transcription of a more efficient Spike S-acyltransferase
The fusogenic activity of SARS-CoV-2 Spike depends on its post-translational lipid modification by host S-acyltransferases, predominantly ZDHHC20. Here, Mesquita and Abrami et al. show that SARS-CoV-2 infection and colitis in mice induce a damage response resulting in an altered version of the ZDHHC20 enzyme that is more abundant and significantly more efficient at attaching fatty acids to viral Spike.
- Francisco S. Mesquita
- , Laurence Abrami
- & F. Gisou van der Goot
-
Article
| Open AccessPRMT2 promotes HIV-1 latency by preventing nucleolar exit and phase separation of Tat into the Super Elongation Complex
The mechanisms regulating Tat function for HIV-1 replication remain poorly understood. Here, the authors reveal that the transcriptional activity of Tat is modulated by a PRMT2-licensed switch between its nucleolar sequestration and phase separation into the nucleoplasmic Super Elongation Complex (SEC) droplets.
- Jiaxing Jin
- , Hui Bai
- & Deqing Hu
-
Article
| Open AccessMePMe-seq: antibody-free simultaneous m6A and m5C mapping in mRNA by metabolic propargyl labeling and sequencing
Methylation is the dominant modification in mRNA and occurs at a variety of sites. Here, Hartstock et al. show that a clickable analogue of the key cosubstrate S-adenosyl-L-methionine (SAM) can be produced in cells, allowing for identification and mapping of different methylated nucleosides in mRNA.
- Katja Hartstock
- , Nadine A. Kueck
- & Andrea Rentmeister
-
Article
| Open AccessHomodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation
CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia progress. Here the authors show that homodimer-mediated phosphorylation of C/EBPα-p42 modulates acute myeloid leukaemia cell differentiation by liquid-liquid phase separation.
- Dongmei Wang
- , Tao Sun
- & Chunyan Ji
-
Article
| Open AccessN-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity
The most common protein modification in eukaryotes is N-terminal acetylation, but its functional impact has remained enigmatic. Here, the authors find that a key role for N-terminal acetylation is shielding proteins from ubiquitin ligase-mediated degradation, mediating motility and longevity.
- Sylvia Varland
- , Rui Duarte Silva
- & Thomas Arnesen
-
Article
| Open AccessMetabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction
How cellular metabolism is connected to differentiation remains poorly understood. Here the authors report a regulatory cascade in which circulating citrate regulates sperm production by controlling protein stability via a specific protein post-translational modification.
- Charlotte M. François
- , Thomas Pihl
- & Bruno Hudry
-
Article
| Open AccessUSP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress
Targeting ribosome biogenesis with the ribosome inhibitor, homoharringtonine (HHT), is effective in leukaemia but not in solid tumours. Here, the authors demonstrate that in solid tumours, activation of JNK signaling following HHT-induced ribosomal stress promotes Snail1 accumulation in the nucleolus which facilitates ribosome biogenesis and resistance to HHT.
- Kewei Qin
- , Shuhan Yu
- & Yong Yi
-
Article
| Open AccessPalmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma
Palmitoylation of proteins can have pathophysiological implications. Here, the authors show that palmitoylation enhances the proteasomal degradation of the histone demethylase PHF2, leading to increased lipogenesis and cell proliferation in an SREBP1c dependent manner and further show that PHF2 acts as an E3 ligase of SREBP1c, suppressing the growth of liver cancer cells.
- Do-Won Jeong
- , Jong-Wan Park
- & Yang-Sook Chun
-
Article
| Open AccessA cyclin-dependent kinase-mediated phosphorylation switch of disordered protein condensation
The authors show that dynamics of protein phosphorylation in the vertebrate cell cycle is largely attributable to CDK-mediated regulation of intrinsically disordered proteins that are involved in biomolecular condensate formation.
- Juan Manuel Valverde
- , Geronimo Dubra
- & Maarten Altelaar
-
Article
| Open AccessAcetylation-dependent coupling between G6PD activity and apoptotic signaling
Lysine acetylation is highly prevalent in metabolic enzymes. Here, the authors highlight the diverse roles of acetylation and show that G6PD acetylation can activate/deactivate G6PD, and promote G6PD ubiquitylation and phosphorylation, its interaction with p53, and p53-dependent pro-apoptotic events.
- Fang Wu
- , Natali H. Muskat
- & Eyal Arbely
-
Article
| Open AccessThe USP46 complex deubiquitylates LRP6 to promote Wnt/β-catenin signaling
Wnt receptors are controlled by their ubiquitin-mediated proteolysis. The authors show that the USP46 deubiquitylase complex potentiates Wnt signaling in human cells, Xenopus, and zebrafish by inhibiting cell surface LRP6 degradation.
- Victoria H. Ng
- , Zachary Spencer
- & Ethan Lee
-
Article
| Open AccessInterferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15
Here the authors show that the basal activation of the interferon/ISG15 pathway is required for the stability of nascent DNA during replication and its upregulation promotes viability, proliferation and acquisition of drug resistance in BRCA1/2 deficient cells.
- Ramona N. Moro
- , Uddipta Biswas
- & Lorenza Penengo
-
Article
| Open AccessA CK2 and SUMO-dependent, PML NB-involved regulatory mechanism controlling BLM ubiquitination and G-quadruplex resolution
The Bloom syndrome helicase (BLM) unwinds a variety of complex DNA structures including G quadruplex. Here the authors report RNF111-ARKL1-dependent ubiquitination of BLM in PML NBs, which limits BLM protein levels and maintains G quadruplex abundance in the nucleus.
- Shichang Liu
- , Erin Atkinson
- & Bin Wang
-
Article
| Open AccessIGF1R-phosphorylated PYCR1 facilitates ELK4 transcriptional activity and sustains tumor growth under hypoxia
Additional roles of metabolic enzymes in cancer remain to be explored. Here, the authors show nuclear localized PYCR1 undergoes IGF1R-mediated phosphorylation under hypoxia, binds with ELK4 and recruits SIRT7 to modulate transcription of target genes to promote colorectal cancer progression.
- Ke Zheng
- , Nannan Sha
- & Tao Chen
-
Article
| Open AccessMulti-omics profiling reveals rhythmic liver function shaped by meal timing
Post-translational modifications (PTMs) couple feed-fast cycles to circadian clocks. Here, the authors systematically profile daily rhythms of the proteome, 4 PTMs and lipidome in mouse livers under TRF, providing a comprehensive resource detailing rhythmic liver functions shaped by meal timing.
- Rongfeng Huang
- , Jianghui Chen
- & Min-Dian Li
-
Article
| Open AccessAn autoinhibited state of 53BP1 revealed by small molecule antagonists and protein engineering
Here, using small molecule antagonists and protein engineering, the authors identify an autoinhibited state of 53BP1 leading to its chromatin binding surface being obstructed. Such small molecule ligands present a potential avenue for the development of cancer therapy drugs.
- Gaofeng Cui
- , Maria Victoria Botuyan
- & Georges Mer
-
Article
| Open AccessNLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85α to drive tumorigenesis
The crosstalk between innate immunity and autophagy plays a critical role in cancer. Here, the authors report that an immune receptor NLRP6 potentiates the PI3K/AKT pathway by selective degradation of p85α. The NLRP6-p85α interaction offers a potential therapeutic target for tumor treatment.
- Feng Zhi
- , Bowen Li
- & Jun Cui
-
Article
| Open AccessSENP6 regulates localization and nuclear condensation of DNA damage response proteins by group deSUMOylation
The authors show that the SUMO protease SENP6 plays an essential role in maintaining genome integrity by disassembling SUMO2/3 polymers from DNA damage response proteins, thereby preventing their trapping at sites of DNA damage and in nuclear condensates.
- Laura A. Claessens
- , Matty Verlaan-de Vries
- & Alfred C. O. Vertegaal
-
Article
| Open AccessSCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity
Cancer stem cells are known to promote hepatocellular carcinoma (HCC) initiation, metastasis and resistance. Here, the authors identify SCARB2 as a driver of tumour-initiating cells via enhanced MYC activity and evaluate the efficacy of targeting this interaction using an FDA approved drug, Polymyxin-B, in preclinical models of HCC.
- Feng Wang
- , Yang Gao
- & Ke Li
-
Article
| Open AccessA chemical catalyst enabling histone acylation with endogenous acyl-CoA
Chemical catalysts that can promote physiologically important post-translational modifications acting as enzyme surrogates have not been reported. Here, the authors develop mBnA, a chemical catalyst that promotes histone lysine acylation in live cells by activating endogenous acyl-CoAs as the only acyl donors.
- Misuzu Habazaki
- , Shinsuke Mizumoto
- & Motomu Kanai
-
Article
| Open AccessBAP1 promotes osteoclast function by metabolic reprogramming
Here, the authors demonstrate that BRCA1-associated protein 1 (Bap1) regulates osteoclast’s capacity to degrade bone. Reprogramming of epigenetic-metabolic axis upon Bap1 loss inhibits bone degradation, preserving bone mass, making it a potential therapeutic target for osteoporosis.
- Nidhi Rohatgi
- , Wei Zou
- & Steven L. Teitelbaum
-
Article
| Open AccessHypoxanthine phosphoribosyl transferase 1 metabolizes temozolomide to activate AMPK for driving chemoresistance of glioblastomas
The metabolism of temozolomide (TMZ) to form methyldiazonium ions and 5-aminoimidazole-4-carboxamide (AICA) results in DNA damage, despite this, resistance frequently occurs in glioblastoma. Here, the authors demonstrate that AICA is further metabolised by HPRT1 into AICAR, which activates AMPK signalling and increases DNA damage repair. Targeting this axis in preclinical glioblastoma models sensitised tumours to TMZ.
- Jianxing Yin
- , Xiefeng Wang
- & Xu Qian
-
Article
| Open AccessA R-loop sensing pathway mediates the relocation of transcribed genes to nuclear pore complexes
Here the authors report that DNA:RNA hybrid-containing R-loop structures are sensed by the ssDNA-binding protein RPA, triggering their relocation to nuclear pore complexes and attenuating transcription-associated genetic instability.
- Arianna Penzo
- , Marion Dubarry
- & Benoit Palancade
-
Article
| Open AccessSer14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male mice
The anti-apoptotic function of Bcl-xL in the heart is diminished by Mst1-mediated phosphorylation of Serine14. Here, the authors show that the Bcl-xL phosphorylation is also promoted by hemodynamic stress, which plays an essential role in mediating compensatory cardiac hypertrophy and contractility.
- Michinari Nakamura
- , Mariko Aoyagi Keller
- & Junichi Sadoshima
-
Article
| Open AccessN-terminal α-amino SUMOylation of cofilin-1 is critical for its regulation of actin depolymerization
SUMOylation plays a key role in modulating protein function. Here, the authors uncover a form of SUMOylation, termed N-αSUMOylation, where SUMO1 attaches to the N-terminus of cofilin1. This SUMOylation promotes cofilin-1 binding to F-actin and cofilin-induced actin depolymerization.
- Weiji Weng
- , Xiaokun Gu
- & Yong Li
-
Article
| Open AccessGut barrier defects, intestinal immune hyperactivation and enhanced lipid catabolism drive lethality in NGLY1-deficient Drosophila
NGLY1 mutations cause a multisystem developmental disorder. Here they show that this enzyme is required for normal gut barrier function, and when mutated, causes immune and metabolic abnormalities, contributing to lethality.
- Ashutosh Pandey
- , Antonio Galeone
- & Hamed Jafar-Nejad
-
Article
| Open AccessCis P-tau is a central circulating and placental etiologic driver and therapeutic target of preeclampsia
Preeclampsia is the leading cause of maternal and fetal mortality worldwide. Here, the authors show that cis P-tau is a central circulating etiologic driver in preeclampsia and that the stereo-specific antibody targeting cis P-tau holds promise for early diagnosis and treatment of the disease.
- Sukanta Jash
- , Sayani Banerjee
- & Surendra Sharma
-
Article
| Open AccessAhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer
An effective response to chemotherapy is often associated with the promotion of type-I interferons and anti-tumor immune responses. Here the authors show that tryptophan metabolites induced by chemo-drugs interfere with STING activation and IFN-I production in bladder cancer, reducing the efficacy of chemotherapy.
- Zikun Ma
- , Zhiyong Li
- & Xiaoyu Liang
-
Article
| Open AccessTAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition
The E1A binding protein p300 and its close paralogue CREB-binding protein are transcriptional coactivators with intrinsic histone acetyltransferase activity. Here, the authors show that the TAZ2 domain of p300 has a HAT autoinhibitory function that is relieved upon binding of transcription factors.
- Longxia Xu
- , Hongwen Xuan
- & Xiaobing Shi
-
Article
| Open AccessFAM3A reshapes VSMC fate specification in abdominal aortic aneurysm by regulating KLF4 ubiquitination
The mechanisms underlying vascular smooth muscle cell reprogramming in abdominal aortic aneurism (AAA) remain unclear. Here they show that FAM3A, a metabolic cytokine, serves as a cell fate-shaping regulator of smooth muscle cells to protect against AAA formation.
- Chuxiang Lei
- , Haoxuan Kan
- & Yuehong Zheng
-
Article
| Open AccessElectrostatic interactions guide substrate recognition of the prokaryotic ubiquitin-like protein ligase PafA
Pupylation is the bacterial equivalent of ubiquitination. Here, the authors show selective binding of the Pup ligase PafA to substrates is driven by tertiary structure features rather than linear motifs and is achieved by a small number of electrostatic interactions, enabling quick adaption to new substrates.
- Matthias F. Block
- , Cyrille L. Delley
- & Eilika Weber-Ban
-
Article
| Open AccessLoss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance
Loss of PP2A activity is often associated with cancer but the underlying mechanism remains unclear. Here, the authors show that decreased methylation of PP2A catalytic C subunit caused by loss of LCMT-1 in prostate cancer abrogates the tumor suppressor activity of PP2A on AR/MED1-dependent gene expression, proposing decreased methyl-PP2A-C as a prognostic marker for prostate cancer progression.
- Reyaz ur Rasool
- , Caitlin M. O’Connor
- & Irfan A. Asangani
-
Article
| Open AccessChemoenzymatic synthesis of genetically-encoded multivalent liquid N-glycan arrays
Cellular glycosylation is complex and heterogeneous, which is challenging to reproduce synthetically. Here, the authors report on enzymatic remodelling of multivalent glycosylated bacteriophages to produce genetically encoded library of N-glycans which can be used to measure glycan-protein interactions with lectins on the surface of live cells and organs.
- Chih-Lan Lin
- , Mirat Sojitra
- & Ratmir Derda
-
Article
| Open AccessCitrullinated fibrinogen-SAAs complex causes vascular metastagenesis
The identification of factors that contribute to pre-metastatic niche can help prevent initial metastasis. Here the authors show that citrullinated fibrinogen complexes with serum amyloid A proteins (SAAs) to form a pre-metastatic niche in patients.
- Yibing Han
- , Takeshi Tomita
- & Sachie Hiratsuka
-
Article
| Open AccessTrim33 masks a non-transcriptional function of E2f4 in replication fork progression
Here the authors show that under replicative stress the E2f4 transcription factor recruits the Recql DNA helicase to facilitate DNA replication. The Trim33 ubiquitin ligase targets E2f4 to limit its interactions with Recql and chromatin.
- Vanessa Rousseau
- , Elias Einig
- & Nikita Popov
-
Article
| Open AccessTRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells
The TRAIP E3 ubiquitin ligase is essential for genome integrity, mutations lead to primordial dwarfism in patients. Here, the authors show that TRAIP degradation in S-phase, results in cell arrest due to DNA damage caused by replication-transcription conflicts.
- Shaun Scaramuzza
- , Rebecca M. Jones
- & Agnieszka Gambus
-
Article
| Open Accessp21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1
PPARα corepressor NCoR1 is a key regulator of fatty acid β-oxidation and ketogenesis. Here, the authors demonstrate that p21-activated kinase 4 phosphorylates NCoR1 at T1619/T2124, resulting in PPARα transrepression and ketone body reduction.
- Min Yan Shi
- , Hwang Chan Yu
- & Eun Ju Bae
-
Article
| Open AccessDeSUMOylation of a Verticillium dahliae enolase facilitates virulence by derepressing the expression of the effector VdSCP8
Verticillium dahliae, a soil-borne fungal pathogen, causes vascular wilt in a wide variety of economically important crops. This study reveals a sophisticated pathogenic mechanism of VdUlpB-deSUMOylated enolase to facilate fungal virulence by derepressing the expression of the effector VdSCP8.
- Xue-Ming Wu
- , Bo-Sen Zhang
- & Hui-Shan Guo