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A role and mechanism for redox sensing by SENP1 in β-cell responses to high fat feeding
Insulin secretion adapts to metabolic needs, but how this happens over the short term is not clear. Here the authors show this involves upregulation of beta-cell exocytosis and requires the SUMO-protease SENP1, which responds to redox state in a zinc-dependent manner.
- Haopeng Lin
- , Kunimasa Suzuki
- & Patrick E. MacDonald
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TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence
Here, the authors show that TRIM28-mediated SUMOylation of SARS-CoV-2 NP is critical for its liquid-liquid phase separation (LLPS) property and subsequent inhibition of innate antiviral immunity. The peptide NSIP-III is applied to unleash such connection by interfering TRIM28 and NP interaction.
- Jiang Ren
- , Shuai Wang
- & Long Zhang
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Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells
Post-translational modifications including protein sumoylation is under specific regulation in glioma stem cells (GSCs). Here, the authors show that Pin1 is deubiquitinated and stabilized by USP34, which in turn promotes isomerization of Ubc9, leading to SUMO1-modified global hypersumoylation to maintain the tumorigenic capacity of GSCs.
- Qiuhong Zhu
- , Panpan Liang
- & Wenchao Zhou
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Characterization 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
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BioE3 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
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A 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
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SENP6 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
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A 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
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N-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
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DeSUMOylation 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
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SUMOylation of Rho-associated protein kinase 2 induces goblet cell metaplasia in allergic airways
Allergic asthma is characterized by goblet cell metaplasia. Here, the authors show protein SUMOylation contributes to goblet cell metaplasia and SUMOylation-mediated ROCK2 activation is an integral component of Rho/ROCK signalling pathway in controlling the airway goblet cell metaplasia.
- Dan Tan
- , Meiping Lu
- & Ximei Wu
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Loss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking adrenal cortex zonal transdifferentiation in mice
SUMOylation is a mechanism of posttranslational modification involved in eukaryotic cell homeostasis. Here the authors report that mice unable to control SUMOylation in the adrenal cortex develop a selective defect in glucocorticoid production due to disrupted differentiation of cells involved in steroid hormone synthesis.
- Damien Dufour
- , Typhanie Dumontet
- & Antoine Martinez
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SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation
The receptor-interacting protein (RIPK1) promotes cell death and contributes to nonalcoholic steatohepatitis pathogenesis. Here the authors report that a SUMO-specific protease, SENP1, deSUMOylates RIPK1 and inhibits cell death in a mouse model of non-alcoholic fatty liver disease.
- Lingjie Yan
- , Tao Zhang
- & Daichao Xu
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Exploration of nuclear body-enhanced sumoylation reveals that PML represses 2-cell features of embryonic stem cells
Here the authors identify novel PML-partners and demonstrate that PML NBs control their sumoylation and that PML-controlled sumoylation of transcriptional regulators maintains the embryonic stem cell transcriptome and transposable element silencing.
- Sarah Tessier
- , Omar Ferhi
- & Valérie Lallemand-Breitenbach
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Suppression of ACE2 SUMOylation protects against SARS-CoV-2 infection through TOLLIP-mediated selective autophagy
SARS- CoV-2 hijacks ACE2 for cell entry. Here, the authors report that dynamic SUMOylation modulates the TOLLIP-directed selective autophagic degradation of ACE2 and suggest SUMOylation inhibition as a potential intervention against SARS-CoV-2 infection.
- Shouheng Jin
- , Xing He
- & Jun Cui
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Deubiquitinating enzymes and the proteasome regulate preferential sets of ubiquitin substrates
Deubiquitinases (DUBs) remove ubiquitin from its target proteins. Here, authors compare the regulatory effects of the proteasome and DUBs on the ubiquitinated proteome. They find preferential sets of substrates regulated by DUBs or by the proteasome. Moreover, they find that PARP1 is hyper-ubiquitinated in response to DUB inhibition, which increases its enzymatic activity.
- Fredrik Trulsson
- , Vyacheslav Akimov
- & Alfred C. O. Vertegaal
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Structural basis for the SUMO protease activity of the atypical ubiquitin-specific protease USPL1
USPL1 is a non-canonical member of the ubiquitin-specific protease (USP) family with activity toward SUMO instead of ubiquitin. Here, the authors present a crystal structure of USPL1 bound to SUMO2, revealing how this enzyme has evolved to bind SUMO as an example of divergent evolution in the USP family.
- Ying Li
- , Nathalia Varejão
- & David Reverter
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Genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma
SUMOylation is a post-translational modification that has been shown to be altered in cancer. Here, the authors show that loss of the SUMO isopeptidase SENP6 leads to unrestricted SUMOylation and genomic instability promoting lymphomagenesis and generating vulnerability to PARP inhibition.
- Markus Schick
- , Le Zhang
- & Ulrich Keller
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Identification of proximal SUMO-dependent interactors using SUMO-ID
Several proteomic approaches allow the analysis of covalent protein SUMOylation, but it remains challenging to systematically study the consequences of a substrate being modified. Here, the authors combine proximity biotinylation and protein-fragment complementation to identify SUMO-dependent protein interactors.
- Orhi Barroso-Gomila
- , Fredrik Trulsson
- & James D. Sutherland
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Sumoylation regulates the assembly and activity of the SMN complex
Sumoylation is important for the assembly and function of the SMN complex, which plays a central role in RNA processing. Here the authors show that loss of this posttranslational modification impairs the ability of SMN to correct selective deficits in the sensory-motor circuit of animal models of spinal muscular atrophy.
- Giulietta M. Riboldi
- , Irene Faravelli
- & Francesco Lotti
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TRIM28 SUMOylates and stabilizes NLRP3 to facilitate inflammasome activation
Post-translational modifications are important regulators of NLRP3 inflammasome activity. Here the authors show that the E3 ligase TRIM28 can SUMOylate NLRP3, thereby limiting its proteasomal degradation and increasing NLRP3 inflammasome activity.
- Ying Qin
- , Qi Li
- & Wei Zhao
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Glucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development
Memory T cells are particularly reliant on fatty acid oxidation as a source of energy. Here the authors show this reliance is controlled by AMPK sensing of glucose deprivation that triggers SENP1-Sirt3 signalling, driving fatty acid oxidation and memory differentiation in T cells via deacetylation of YME1L1 to induce mitochondrial fusion.
- Jianli He
- , Xun Shangguan
- & Jinke Cheng
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SUMOylation controls the binding of hexokinase 2 to mitochondria and protects against prostate cancer tumorigenesis
The oncogenic activity of Hexokinase 2, the first rate-limiting enzyme of glycolysis, requires its mitochondrial localization. Here, the authors show that SUMOylation of hexokinase 2 disrupts its binding to mitochondria and protects cells from tumorigenesis in prostate cancer.
- Xun Shangguan
- , Jianli He
- & Wei Xue
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Quantitative SUMO proteomics identifies PIAS1 substrates involved in cell migration and motility
PIAS1 is an E3 SUMO ligase involved in various cellular processes. Here, the authors use quantitative proteomics to identify potential PIAS1 substrates in human cells and elucidate the biological consequences of PIAS1-mediated SUMOylation of vimentin.
- Chongyang Li
- , Francis P. McManus
- & Pierre Thibault
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The ubiquitin-like modifier FAT10 interferes with SUMO activation
FAT10 is an ubiquitin-like modifier that targets proteins to proteasomal degradation. Here, the authors show that FAT10 also regulates SUMO activation in vitro and in cells, providing evidence for functional crosstalk between two ubiquitin-like modifiers.
- Annette Aichem
- , Carolin Sailer
- & Marcus Groettrup
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The poly-SUMO2/3 protease SENP6 enables assembly of the constitutive centromere-associated network by group deSUMOylation
While the biological roles of ubiquitin chains are well studied, little is known about the functions of SUMO polymers. Here, the authors identify poly-SUMOylation substrates and provide evidence that SUMO polymers regulate the accumulation of CCAN subunits at chromatin and centromeres.
- Frauke Liebelt
- , Nicolette S. Jansen
- & Alfred C. O. Vertegaal
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hCINAP regulates the DNA-damage response and mediates the resistance of acute myelocytic leukemia cells to therapy
Acute myeloid leukemia cells are often resistant to radiotherapy and chemotherapy. Here, the authors suggest that hCINAP contributes to the resistance of acute myeloid leukemia cells by regulating SUMOylation of Nucleophosmin during the DNA-damage response.
- Ruidan Xu
- , Shuyu Yu
- & Xiaofeng Zheng
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Arkadia/RNF111 is a SUMO-targeted ubiquitin ligase with preference for substrates marked with SUMO1-capped SUMO2/3 chain
The cellular functions of poly-SUMO chains of different compositions are not fully understood. Here, the authors characterize Arkadia/RNF111 as a SUMO-targeted ubiquitin ligase that recognizes proteins with hybrid SUMO1-capped SUMO2/3 chains and targets them for proteasomal degradation.
- Annie M. Sriramachandran
- , Katrin Meyer-Teschendorf
- & R. Jürgen Dohmen
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Distinct adaptive mechanisms drive recovery from aneuploidy caused by loss of the Ulp2 SUMO protease
Transient aneuploidy enables cells to survive sudden environmental changes before longterm cellular adaptations are established. Here, the authors show that yeast cells respond to the acute loss of Ulp2 SUMO protease by rapid induction of aneuploidy, and reveal predictable long-term adaptation mechanisms that restore euploidy.
- Hong-Yeoul Ryu
- , Francesc López-Giráldez
- & Mark Hochstrasser
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Article
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Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme
Ubiquitin and ubiquitin-like modifiers such as SUMO play important roles in several cellular pathways that can become deregulated in cancer. Here the authors describe the structural basis for inhibition of SUMO E1 ligase by the small molecule COH000.
- Zongyang Lv
- , Lingmin Yuan
- & Shaun K. Olsen
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Sumoylation of RORγt regulates TH17 differentiation and thymocyte development
The transcription factor RORγt is essential for the differentiation of TH17 cells, thymocyte development and lymphoid organogenesis. Here the authors show that the function of RORγt is regulated by PIAS4-mediated sumoylation that stabilize the interaction with SRC1 and KAT2A, to enhance the transcriptional activity of RORγt.
- Zhiheng He
- , Jing Zhang
- & Zuoming Sun
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An E2-ubiquitin thioester-driven approach to identify substrates modified with ubiquitin and ubiquitin-like molecules
Ubiquitination and ubiquitin-like modifications of proteins regulate multiple cellular processes but identifying substrates of specific E2 and E3 enzymes remains challenging. Here, the authors conjugate E2 enzymes with enrichable ubiquitin derivatives to identify substrates of specific E2/E3 pairs by mass spectrometry.
- Gábor Bakos
- , Lu Yu
- & Jörg Mansfeld
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SUMOylation of ROR-γt inhibits IL-17 expression and inflammation via HDAC2
Interleukin-17 (IL-17)-secreting CD4 T cells (Th17) are induced by the master transcription factor RORγt, and are important for anti-fungal immunity and inflammatory responses. Here the authors show that Ubc9-mediated SUMOylation of RORγt induces HDAC2 binding to IL-17 promoter for suppressing IL-17 production in Th17 cells.
- Amir Kumar Singh
- , Prashant Khare
- & K. Venuprasad
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Article
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ATR/Chk1 signaling induces autophagy through sumoylated RhoB-mediated lysosomal translocation of TSC2 after DNA damage
DNA damage can lead to autophagy. Here the authors reveal a molecular mechanism for ATR/Chk1 signaling-induced autophagy in response to DNA damage, through an ATR/Chk1/RhoB-mediated lysosomal recruitment of TSC complex and subsequent mTORC1 inhibition.
- Mingdong Liu
- , Taoling Zeng
- & Hong-Rui Wang
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SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis
VEGFR2 is a central regulator of angiogenesis. Here Zhou et al. report that SUMOylation of VEGFR2 regulates its subcellular localisation and activity, and that endothelial-specific knockout of the SUMO endopeptidase SENP1 protects against VEGFR2-mediated pathological angiogenesis.
- Huanjiao Jenny Zhou
- , Zhe Xu
- & Wang Min
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Article
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Site-specific characterization of endogenous SUMOylation across species and organs
Proteomics is a powerful method to study protein SUMOylation, but system-wide insights into endogenous SUMO2/3 modification events are still sparse. Here, the authors develop a more sensitive SUMO proteomics approach, providing detailed maps of endogenous SUMO2/3 sites in human cells and mouse tissues.
- Ivo A. Hendriks
- , David Lyon
- & Michael L. Nielsen
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Article
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RING tetramerization is required for nuclear body biogenesis and PML sumoylation
Promyelocytic leukemia protein (PML) is a scaffolding protein that organizes PML nuclear bodies. Here the authors present the tetrameric crystal structure of the PML RING domain and show that RING tetramerization is functionally important for nuclear body formation and PML sumoylation.
- Pengran Wang
- , Shirine Benhenda
- & Guoyu Meng
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Article
| Open Access
SUMO targets the APC/C to regulate transition from metaphase to anaphase
Signal transduction by small ubiquitin-like modifier (SUMO) is important for cell cycle progression. Here the authors show that SUMOylation regulates the APC/C complex, a master orchestrator of metaphase to anaphase transition, with consequences for mitotic progression.
- Karolin Eifler
- , Sabine A. G. Cuijpers
- & Alfred C. O. Vertegaal
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Article
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Sumoylation regulates FMRP-mediated dendritic spine elimination and maturation
Fragile X syndrome patients display intellectual disability and autism, caused by mutations in the RNA-binding protein fragile X mental retardation protein (FMRP). Here, the authors show that FMRP sumoylation is required for regulating spine density and maturation.
- Anouar Khayachi
- , Carole Gwizdek
- & Stéphane Martin
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| Open Access
Site-specific identification and quantitation of endogenous SUMO modifications under native conditions
SUMOylation is post-translational modification implicated in several biological pathways. Here the authors describe an approach for the global profiling of SUMO attachment sites under native conditions that also allows the parallel determination of SUMO and Ub attachments.
- Ryan J. Lumpkin
- , Hongbo Gu
- & Elizabeth A. Komives
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Article
| Open Access
HSP70-Hrd1 axis precludes the oncorepressor potential of N-terminal misfolded Blimp-1s in lymphoma cells
The transcriptional repressor Blimp-1 has an important role in B-cell differentiation. Here the authors show that lymphoma-associated Blimp-1 mutants are selectively recognized by HSP70-Hrd1, which leads to their accelerated degradation and propose HSP70 inhibition as a therapeutic approach for certain lymphomas.
- Wen-Fang Wang
- , Li Yan
- & Jiang Zhu
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Article
| Open Access
DNA end resection requires constitutive sumoylation of CtIP by CBX4
The choice between non-homologous end-joining and homologous recombination to repair a DNA double-strand break depends on activation of the end resection machinery. Here the authors show that SUMO E3 ligase CBX4 sumoylates subpopulation of CtIP to regulate recruitment to breaks and resection.
- Isabel Soria-Bretones
- , Cristina Cepeda-García
- & Pablo Huertas
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Article
| Open Access
The critical role of SENP1-mediated GATA2 deSUMOylation in promoting endothelial activation in graft arteriosclerosis
A major cause of transplanted organ failure is graft arteriosclerosis. Qiuet al. show that a key protease of post-translational SUMO modification, SENP1, is crucial for graft arteriosclerosis by regulating the activity of GATA2 transcription factor in the endothelium, and promoting endothelial inflammation and alloimmunity.
- Cong Qiu
- , Yuewen Wang
- & Luyang Yu
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Article
| Open Access
Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation
Gluconeogenesis is downregulated in hepatocellular carcinoma. Here, the authors show that nuclear receptor Nur77 acts as a tumour suppressor sustaining gluconeogenesis by enhancing phosphoenolpyruvate carboxykinase (PEPCK1) stability via regulating its interaction with the SUMO-conjugating enzyme Ubc9.
- Xue-li Bian
- , Hang-zi Chen
- & Qiao Wu
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Article
| Open Access
Rad18-dependent SUMOylation of human specialized DNA polymerase eta is required to prevent under-replicated DNA
Translesion synthesis polymerase eta has a well characterized role in replicating past UV-induced DNA lesions and has recently been shown to act at difficult to replicate sequences. Here the authors show that its SUMOylation is required to recruit pol eta at the replication fork and to prevent under-replicated DNA.
- Emmanuelle Despras
- , Méghane Sittewelle
- & Patricia L Kannouche
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Article
| Open Access
SUMOylated NKAP is essential for chromosome alignment by anchoring CENP-E to kinetochores
The kinetochore-bound motor CENP-E plays a critical role in chromosome alignment. Here, the authors show that NF-κB activating protein (NKAP) dynamically localises to kinetochores, is SUMOylated during mitosis, and this modification is required for NKAP to bind CENP-E and localise CENP-E to the kinetochore.
- Teng Li
- , Liang Chen
- & Qing Xia
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Article
| Open Access
The methyltransferase Suv39h1 links the SUMO pathway to HP1α marking at pericentric heterochromatin
The Suv39h histone methyltransferases promote trimethylation of histone H3 on lysine 9 (H3K9me3). Here, in the Suv39h1 paralog, the authors identify an enhancer of HP1a sumoylation activity that impacts heterochromatin.
- Christèle Maison
- , Delphine Bailly
- & Geneviève Almouzni
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Article
| Open Access
Critical role of RanBP2-mediated SUMOylation of Small Heterodimer Partner in maintaining bile acid homeostasis
As signalling molecules, bile acids (BAs) can affect metabolism, but due to detergent-like properties, BA levels must be tightly regulated. Here, Kim et al.show that RanBP2, a nucleoporin, maintains BA homoeostasis through SUMOylation of Small Heterodimer Partner (SHP), an orphan nuclear receptor.
- Dong-Hyun Kim
- , Sanghoon Kwon
- & Jongsook Kim Kemper
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Article
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MeCP2 SUMOylation rescues Mecp2-mutant-induced behavioural deficits in a mouse model of Rett syndrome
Post-translational modifications of methyl-CpG-binding protein 2 (MeCP2) are important for its function and dysfunction in Rett syndrome. Here, Tai et al. show a functional interaction between MeCP2 SUMOylation and phosphorylation in rodent behavior and synaptic plasticity.
- Derek J. C. Tai
- , Yen C. Liu
- & Eminy H. Y. Lee
Dynamics of DNA damage-induced nuclear inclusions are regulated by SUMOylation of Btn2