Affinage

SENP5

Sentrin-specific protease 5 · UniProt Q96HI0

Length
755 aa
Mass
86.7 kDa
Annotated
2026-06-10
27 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SENP5 is a SUMO-specific protease that couples deSUMOylation to cell cycle progression, mitochondrial dynamics, and stress signaling (PMID:16738315, PMID:19411255). Biochemically it possesses both SUMO C-terminal hydrolase and isopeptidase activities and preferentially processes and removes SUMO-2/3 over SUMO-1 (PMID:16738315); crystal structures of the catalytic domain bound to SUMO1 and SUMO2 explain this selectivity through a basic patch centered on Arg624, which engages Asp63 of SUMO2/3 more favorably than the equivalent Glu67 of SUMO1 (PMID:40404649). Full-length SENP5 is anchored in the granular component of the nucleolus through its N-terminal non-catalytic domain and through binding to B23/nucleophosmin, which is required for its stable accumulation and for nucleolar SUMO homeostasis and ribosome biogenesis (PMID:16738315, PMID:19015314). At the G2/M transition SENP5 relocates from the nucleolus to the mitochondrial surface, where it deSUMOylates DRP1 to enlarge the labile, fission-competent DRP1 pool and drive mitochondrial fragmentation; loss of SENP5 stalls this redistribution, arrests the cell cycle, and elevates ROS (PMID:17341580, PMID:19411255), a mitochondria-targeted role confirmed in transgenic hearts where SENP5 overexpression reduces DRP1 SUMOylation and produces cardiomyopathy rescuable by Bcl2 (PMID:25128087). Beyond mitochondria, SENP5 acts on a panel of substrates: it deSUMOylates Aurora A to restrain its kinase activity during spindle assembly (PMID:34313310), deSUMOylates H2AZ to promote homologous-recombination DNA repair (PMID:37684630), and stabilizes CDK1 by preventing its ubiquitin-proteasomal degradation to support G2/M progression (PMID:40474290). RNAi depletion blocks proliferation and causes binucleate cells and cytokinesis failure, establishing SENP5 as essential for mitosis (PMID:16738315).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2006 High

    Established SENP5 as a catalytically active SUMO protease with isoform preference and an essential mitotic function, defining the enzyme's basic activity and a localization-determining N-terminal domain.

    Evidence In vitro SUMO processing/isopeptidase assays with defined substrates, deletion mutagenesis, and RNAi with cytological phenotyping

    PMID:16738315

    Open questions at the time
    • Did not resolve the structural basis of SUMO2/3 preference
    • Did not identify physiological substrates beyond model RanGAP1
  2. 2007 High

    Identified a cytosolic/mitochondrial pool of SENP5 that deSUMOylates DRP1, placing the enzyme directly in control of mitochondrial fission and ROS.

    Evidence Overexpression and siRNA with immunofluorescence, ROS measurement, and epistatic rescue using dominant-negative DRP1 / DRP1 siRNA

    PMID:17341580

    Open questions at the time
    • Did not explain how SENP5 reaches the mitochondrial surface
    • Other mitochondrial SUMO substrates not delineated
  3. 2008 High

    Showed that B23/nucleophosmin tethers and stabilizes SENP5 in the nucleolus, linking the enzyme to nucleolar SUMO homeostasis and ribosome biogenesis.

    Evidence Co-immunoprecipitation in Xenopus egg extracts, depletion in mammalian cells, immunofluorescence, and ribosome biogenesis assays

    PMID:19015314

    Open questions at the time
    • Nucleolar SUMO substrates of SENP5 not individually identified
    • Redundancy with SENP3 not fully separated
  4. 2009 High

    Resolved the spatiotemporal logic of SENP5 action by showing G2/M-coupled translocation from nucleolus to mitochondria that triggers DRP1 deSUMOylation and fragmentation.

    Evidence Live-cell imaging/immunofluorescence across the cell cycle with siRNA and cell cycle analysis

    PMID:19411255

    Open questions at the time
    • Trigger and receptor for mitochondrial recruitment unknown
    • Mechanism coupling translocation to checkpoint timing unresolved
  5. 2014 High

    Validated the SENP5-DRP1 axis in vivo and tied it to organ-level pathology, showing cardiac consequences of altered mitochondrial SUMOylation.

    Evidence Transgenic mouse cardiac overexpression with DRP1 SUMOylation Western blots, mitochondrial morphology, and Bcl2 genetic rescue

    PMID:25128087

    Open questions at the time
    • Loss-of-function (knockout) cardiac phenotype not tested
    • Direct causal step from DRP1 SUMO state to apoptosis not fully mapped
  6. 2014 Medium

    Extended SENP5 into cancer biology by linking it to TGFβRI-MMP9-driven breast cancer invasion.

    Evidence siRNA knockdown with invasion/migration/proliferation assays and Western blot for TGFβRI and MMP9

    PMID:24658161

    Open questions at the time
    • No direct SUMOylation of TGFβRI demonstrated
    • Single lab; mechanism downstream of SENP5 inferred from pathway readouts
  7. 2016 Medium

    Connected SENP5 to the DNA damage response by identifying ATRIP as a deSUMOylation substrate required for ATR checkpoint activation.

    Evidence In vivo SUMOylation assay, co-IP, siRNA, clonogenic survival after IR/etoposide, and checkpoint Western blots in HCC cells

    PMID:27649656

    Open questions at the time
    • Single lab; no in vitro reconstitution of ATRIP deSUMOylation
    • SUMO acceptor site on ATRIP not mapped
  8. 2018 Medium

    Demonstrated neuronal subcellular targeting of SENP5 to synapses and axonal mitochondria, distinguishing it from nuclear-restricted SENP3.

    Evidence Immunohistochemistry, double immunolabeling, and immunoelectron microscopy in mouse brain and cultured neurons

    PMID:29277914

    Open questions at the time
    • No functional consequence demonstrated in this study
    • Synaptic substrates of SENP5 not identified
  9. 2021 High

    Defined Aurora A as a SUMO2-modified substrate whose deSUMOylation by SENP5 restrains kinase activity to ensure proper spindle assembly and chromosome segregation.

    Evidence In vivo/in vitro SUMOylation-deSUMOylation assays, K258 mutagenesis, kinase assays, RNAi, and rescue by Aurora A inhibition

    PMID:34313310

    Open questions at the time
    • Relative contributions of SENP3 vs SENP5 not separated
    • Timing of Aurora A deSUMOylation across mitosis not resolved
  10. 2021 Medium

    Revealed a catalytically dead Senp5 splice variant that competitively dampens DRP1 deSUMOylation, adding an isoform-balance layer controlling mitochondrial/ER morphology and cortical neuron migration.

    Evidence Splice variant expression, SUMOylation assays, organelle morphology, dominant-negative competition, and in utero electroporation

    PMID:34988397

    Open questions at the time
    • Single lab; endogenous regulation of variant ratio not established
    • Direct competition mechanism not biochemically reconstituted
  11. 2023 High

    Placed SENP5 in DNA repair via H2AZ deSUMOylation, promoting homologous recombination and modulating radiosensitivity in colorectal cancer.

    Evidence SUMO-proteomic MS, co-IP, siRNA, comet/IF assays, and patient-derived organoid and xenograft models

    PMID:37684630

    Open questions at the time
    • H2AZ SUMO site and its repair-coupled dynamics not detailed
    • Interplay with the ATRIP-ATR arm not addressed
  12. 2023 Medium

    Linked SENP5 to transcriptional stress signaling by showing it lowers E2F1 SUMOylation to raise E2F1 levels and activate p53 in traumatic brain injury.

    Evidence siRNA in a TBI rat model, Western blot for E2F1 SUMOylation, p53 pathway readouts, and E2F1 epistasis rescue

    PMID:37403456

    Open questions at the time
    • Single lab; no in vitro deSUMOylation reconstitution
    • Direct E2F1 SUMO acceptor site not defined
  13. 2025 High

    Provided the structural explanation for SUMO2/3 selectivity, identifying Arg624 at the catalytic interface as the discriminating residue.

    Evidence X-ray crystallography of SENP5-SUMO1 and SENP5-SUMO2 complexes with swapping mutagenesis

    PMID:40404649

    Open questions at the time
    • Structure of full-length enzyme with regulatory N-terminus not solved
    • Substrate-specific recognition beyond the SUMO moiety not addressed
  14. 2025 Medium

    Showed SENP5 stabilizes CDK1 by deSUMOylation-dependent protection from proteasomal degradation, reinforcing its role in G2/M progression in breast cancer.

    Evidence Co-IP, fluorescence co-localization, Western blot, siRNA, proliferation assays, and CDK1-inhibitor combination xenografts

    PMID:40474290

    Open questions at the time
    • Single lab; CDK1 SUMO acceptor site and responsible ligase not defined
    • Direct in vitro deSUMOylation not reconstituted
  15. 2025 Medium

    Implicated SENP5 in β-catenin stabilization and GPX4-mediated ferroptosis resistance in endometrial cancer.

    Evidence Co-IP, SUMOylation analysis, knockdown/overexpression, C11-BODIPY ferroptosis assay, and Western blot

    PMID:40410883

    Open questions at the time
    • Single lab; β-catenin SUMO site not mapped
    • Mechanism connecting β-catenin to GPX4 not fully dissected
  16. 2026 Medium

    Extended SENP5-Aurora A regulation to antiviral immunity, showing deSUMoylated AURKA relieves PP2A-mediated suppression of STAT2 phosphorylation.

    Evidence siRNA/overexpression, immunoprecipitation, STAT2 phospho-Western, viral replication, and PP2A activity assays

    PMID:41827042

    Open questions at the time
    • Single lab; in vivo antiviral relevance not established
    • Direct chain of AURKA SUMO state to PP2A activity not biochemically resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SENP5 recruitment to mitochondria is triggered at G2/M and how it selects among its many substrates in different compartments remains unresolved.
  • No identified receptor or signal for the nucleolus-to-mitochondria translocation
  • No structure of the full-length enzyme explaining substrate (vs SUMO-moiety) recognition
  • Substrate prioritization across nucleolar, mitochondrial, and chromatin pools not understood

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 1
Localization
GO:0005730 nucleolus 3 GO:0005739 mitochondrion 3 GO:0005829 cytosol 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-73894 DNA Repair 2 R-HSA-8953854 Metabolism of RNA 2
Partners
ATRIPAURKAB23/NPM1CDK1CTNNB1DRP1E2F1H2AZ

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 SENP5 has SUMO C-terminal hydrolase and SUMO isopeptidase activities; its catalytic domain preferentially processes SUMO-2/3 precursors over SUMO-1, and preferentially removes SUMO-2 and SUMO-3 from SUMO-modified RanGAP1 in vitro. Full-length SENP5 localizes to the nucleolus via its N-terminal non-catalytic domain; deletion of this domain leads to loss of nucleolar localization and increased de-SUMOylation activity in vivo. Knockdown of SENP5 by RNAi causes increased SUMO-1 and SUMO-2/3 conjugates, inhibition of cell proliferation, defects in nuclear morphology, and binucleate cell formation, establishing an essential role in mitosis/cytokinesis. In vitro SUMO processing and isopeptidase assays; cotransfection assays; deletion mutagenesis; RNA interference knockdown with flow cytometry and microscopy Molecular and cellular biology High 16738315
2007 The cytosolic pool of SENP5 catalyzes deSUMOylation of SUMO1 from mitochondrial substrates including DRP1. Overexpression of SENP5 rescues SUMO1-induced mitochondrial fragmentation partly by downregulating DRP1 SUMOylation. Silencing SENP5 results in fragmented mitochondria with stably mono-SUMOylated DRP1, increased DRP1-mediated fission, and significantly elevated ROS production. Re-expression of dominant-negative DRP1 or silencing DRP1 rescues both morphological and ROS phenotypes caused by SENP5 knockdown. Overexpression and siRNA knockdown; immunofluorescence microscopy; ROS measurement; genetic rescue with dominant-negative DRP1 or DRP1 siRNA Journal of cell science High 17341580
2008 B23/nucleophosmin binds SENP3 and SENP5 in Xenopus laevis egg extracts and is essential for stable accumulation of SENP3 and SENP5 in mammalian tissue culture cells. Both SENP3 and SENP5 localize to the granular component of the nucleolus. Codepletion of SENP3 and SENP5, or depletion of B23/nucleophosmin, causes accumulation of SUMO proteins within nucleoli and defects in ribosome biogenesis. Co-immunoprecipitation in Xenopus egg extracts; depletion experiments in mammalian cells; immunofluorescence localization; ribosome biogenesis assays The Journal of cell biology High 19015314
2009 During the G2/M transition (prior to nuclear envelope breakdown), SENP5 translocates from the nucleolus to the mitochondrial surface. This recruitment leads to a significant loss of mitochondrial SUMOylation, an increase in the labile (unmodified) pool of DRP1, and mitochondrial fragmentation. Silencing of SENP5 arrests the cell cycle precisely at the time when the protease would normally translocate to mitochondria. Live-cell imaging and immunofluorescence during cell cycle progression; siRNA knockdown; cell cycle analysis The Journal of biological chemistry High 19411255
2014 Cardiac overexpression of SENP5 in transgenic mice leads to decreased SUMO attachment to DRP1, resulting in larger mitochondria at early developmental stages, decreased cardiomyocyte proliferation, elevated apoptosis, and cardiac dysfunction consistent with cardiomyopathy. Overexpression of Bcl2 in SENP5-Tg hearts improved cardiac function, supporting a mitochondria-targeted mechanism of SENP5 action in vivo. Transgenic mouse overexpression; Western blot for DRP1 SUMOylation; mitochondrial morphology analysis; genetic rescue with Bcl2 overexpression Journal of molecular and cellular cardiology High 25128087
2014 SENP5 silencing inhibits anchorage-independent growth, proliferation, migration, and invasion in breast cancer cell lines. These effects are mediated through regulation of TGFβRI levels and downstream MMP9 expression, establishing a SENP5–TGFβRI–MMP9 cascade in breast cancer invasion. siRNA knockdown; invasion/migration/proliferation assays; Western blot for TGFβRI and MMP9 Oncotarget Medium 24658161
2016 SENP5 interacts with ATRIP (ATR-interacting protein) and promotes deSUMOylation of ATRIP in HCC cells. SENP5 depletion causes hypersensitivity to ionizing radiation and etoposide with defective ATR checkpoint activation (decreased ATR activation and phosphorylation of ATR targets), linking SENP5-mediated deSUMOylation of ATRIP to DNA damage response. In vivo SUMOylation assay; co-immunoprecipitation; siRNA knockdown; clonogenic survival after IR/etoposide; checkpoint activation by Western blot European review for medical and pharmacological sciences Medium 27649656
2018 In the adult mouse brain, SENP5 localizes to pre- and post-synaptic structures and to mitochondria within axon terminals, as determined by immunofluorescence co-labeling with synaptic markers and immunoelectron microscopy. SENP3, by contrast, is confined to the nucleus, demonstrating differential subcellular localization of these related SENPs in neurons. Immunohistochemistry; double immunolabeling in cultured neurons; immunoelectron microscopy The Journal of comparative neurology Medium 29277914
2021 SUMO conjugation of Aurora A (AurA) at K258 by SUMO2 promotes AurA kinase activity and facilitates binding with its activator Bora in early mitosis. SENP3 and SENP5 deSUMOylate AurA; knockdown of SENP3 and SENP5 leads to increased AurA kinase activity and abnormalities in spindle assembly and chromosome segregation, which are rescued by suppressing AurA kinase activity. In vivo and in vitro SUMOylation/deSUMOylation assays; site-directed mutagenesis (K258); kinase activity assays; RNAi knockdown; spindle assembly and chromosome segregation analysis; genetic rescue with AurA kinase inhibition Journal of cell science High 34313310
2021 A splice variant of Senp5 (Senp5S) lacks peptidase activity and competes against active Senp5L (and other SENPs) to prevent deSUMOylation of Drp1, thereby altering the SUMOylation balance of Drp1 and affecting mitochondrial morphology, Drp1 ubiquitination, and ER tubulation. The Senp5L/Senp5S balance controls neuronal polarization and migration during cerebral cortex development. Expression of splice variants; SUMOylation assays; mitochondrial and ER morphology analysis; dominant-negative competition experiments; in utero electroporation for cortical migration analysis iScience Medium 34988397
2023 SENP5 promotes homologous recombination (HR)-mediated DNA damage repair in colorectal cancer cells by deSUMOylating H2AZ. SUMO proteomic mass spectrometry combined with co-immunoprecipitation identified H2AZ as a deSUMOylation substrate of SENP5. SENP5 knockdown increases radiosensitivity in CRC cells in vitro and in patient-derived organoid and xenograft models. SUMO-proteomic mass spectrometry; co-immunoprecipitation; siRNA knockdown; comet assay; immunofluorescence; apoptosis/cell cycle analysis; patient-derived organoid and xenograft models Journal of experimental & clinical cancer research : CR High 37684630
2023 SENP5 inhibits SUMOylation of E2F1 (transcription factor 1), increasing E2F1 protein expression. Elevated E2F1 activates the p53 signaling pathway in the context of traumatic brain injury. Silencing E2F1 blocks p53 pathway activation, and overexpression of E2F1 partially reverses the protective effect of SENP5 knockdown in TBI rats. siRNA knockdown in TBI rat model; Western blot for SUMOylation of E2F1; p53 pathway activation analysis; epistasis rescue with E2F1 overexpression Acta biochimica et biophysica Sinica Medium 37403456
2025 Crystal structures of human SENP5 catalytic domain in complex with both SUMO1 and SUMO2 isoforms reveal a minimal complex interface. SENP5's preference for SUMO2/3 over SUMO1 is attributable to a basic patch centered on Arg624: Arg624 interacts favorably with Asp63 in SUMO2/3, but less favorably with the equivalent Glu67 in SUMO1. Swapping mutagenesis at this interface confirmed the structural basis of isoform selectivity. X-ray crystallography of SENP5–SUMO1 and SENP5–SUMO2 complexes; swapping mutagenesis; structural analysis Nature communications High 40404649
2025 SENP5 mediates deSUMOylation of CDK1, reducing CDK1 degradation via the ubiquitin-proteasome pathway and thereby increasing CDK1 protein levels to promote cell cycle G2/M progression in breast cancer cells. Co-immunoprecipitation and fluorescence co-localization studies confirmed interaction between SENP5 and CDK1. Co-immunoprecipitation; fluorescence co-localization; Western blot; siRNA knockdown; CCK8/colony/EdU/wound healing/transwell assays; CDK1 inhibitor combination in xenograft model Breast cancer research : BCR Medium 40474290
2025 SENP5 promotes deSUMOylation of β-catenin in endometrial cancer cells, stabilizing β-catenin protein levels. Stabilized β-catenin upregulates GPX4, conferring resistance to ferroptosis and promoting cell proliferation. Co-immunoprecipitation and SUMOylation analysis confirmed β-catenin as a direct deSUMOylation substrate of SENP5. Co-immunoprecipitation; SUMOylation analysis; siRNA knockdown and overexpression; CCK8; EDU; C11-BODIPY ferroptosis assay; Western blot European journal of medical research Medium 40410883
2026 SENP5-mediated deSUMOylation of Aurora kinase A (AURKA) alleviates AURKA's suppression of STAT2 phosphorylation. AURKA suppresses STAT2 phosphorylation by enhancing the activity of protein phosphatase PP2A. By deSUMOylating AURKA, SENP5 promotes STAT2 phosphorylation in the JAK-STAT pathway and enhances antiviral innate immune responses against VSV and HSV-1. siRNA knockdown; overexpression; immunoprecipitation; Western blot for STAT2 phosphorylation; viral replication assays; PP2A activity assay Cell communication and signaling : CCS Medium 41827042

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 The SUMO protease SENP5 is required to maintain mitochondrial morphology and function. Journal of cell science 222 17341580
2006 The SUMO-specific protease SENP5 is required for cell division. Molecular and cellular biology 148 16738315
2009 Translocation of SenP5 from the nucleoli to the mitochondria modulates DRP1-dependent fission during mitosis. The Journal of biological chemistry 136 19411255
2008 Nucleolar protein B23/nucleophosmin regulates the vertebrate SUMO pathway through SENP3 and SENP5 proteases. The Journal of cell biology 95 19015314
2014 SENP5, a SUMO isopeptidase, induces apoptosis and cardiomyopathy. Journal of molecular and cellular cardiology 68 25128087
2019 Saikosaponin-d Inhibits the Hepatoma Cells and Enhances Chemosensitivity Through SENP5-Dependent Inhibition of Gli1 SUMOylation Under Hypoxia. Frontiers in pharmacology 49 31616295
2006 SUMO-specific proteases and the cell cycle. An essential role for SENP5 in cell proliferation. Cell cycle (Georgetown, Tex.) 41 17102611
2008 Overexpression of SENP5 in oral squamous cell carcinoma and its association with differentiation. Oncology reports 38 18949399
2016 The SUMO-specific protease SENP5 controls DNA damage response and promotes tumorigenesis in hepatocellular carcinoma. European review for medical and pharmacological sciences 34 27649656
2014 SENP5 mediates breast cancer invasion via a TGFβRI SUMOylation cascade. Oncotarget 33 24658161
2021 Drp1 SUMO/deSUMOylation by Senp5 isoforms influences ER tubulation and mitochondrial dynamics to regulate brain development. iScience 32 34988397
2023 SENP5 promotes homologous recombination-mediated DNA damage repair in colorectal cancer cells through H2AZ deSUMOylation. Journal of experimental & clinical cancer research : CR 27 37684630
2014 Inhibition of SENP5 suppresses cell growth and promotes apoptosis in osteosarcoma cells. Experimental and therapeutic medicine 23 24926368
2018 Synaptic localization of the SUMOylation-regulating protease SENP5 in the adult mouse brain. The Journal of comparative neurology 12 29277914
2020 Zinc deficiency induces abnormal development of the myocardium by promoting SENP5 overexpression. PloS one 10 33211757
2021 SUMO proteases SENP3 and SENP5 spatiotemporally regulate the kinase activity of Aurora A. Journal of cell science 7 34313310
2024 Peptidylprolyl isomerase A guides SENP5/GAU1 DNA-lncRNA triplex generation for driving tumorigenesis. Nature communications 6 39433793
2023 SENP5 deteriorates traumatic brain injury via SUMO2-dependent suppression of E2F1 SUMOylation. Acta biochimica et biophysica Sinica 6 37403456
2015 Linking the SUMO protease SENP5 to neutrophil differentiation of AML cells. Leukemia research reports 5 25984443
2025 Structural basis for the human SENP5's SUMO isoform discrimination. Nature communications 4 40404649
2025 SENP5 promotes endometrial cancer cell growth by regulating β-catenin deSUMOylation to enhance GPX4-resistance to ferroptosis. European journal of medical research 2 40410883
2024 Inhibition of SENP5 reduces brain injury in TBI rats by regulating NEDD4L/TCF3 axis. The International journal of neuroscience 1 38712596
2026 SENP5 enhances antiviral innate immunity by promoting AURKA-dependent STAT2 phosphorylation. Cell communication and signaling : CCS 0 41827042
2025 SENP5 drives breast cancer progression through deSUMOYlation of CDK1. Breast cancer research : BCR 0 40474290
2025 SENP5 Attenuates LPS-Induced Acute Lung Injury by Inhibiting Apoptosis of Lung Epithelial Cells Through SLC7A5/mTOR Signaling Pathway. Frontiers in bioscience (Landmark edition) 0 41198555
2025 SUMOylation involved in malignant progression of multiple tumors and SENP5 may improve the chemotherapy sensitivity of hypoxic tumors. Frontiers in pharmacology 0 41268439
2025 SENP5 acts as a downstream target of androgen receptor and contributes to prostate cancer growth. Oncology letters 0 41383972

Missed literature

Know a paper Affinage missed for SENP5? Flag it for the maintainers and the community.

No submissions yet.