Affinage

SENP7

Sentrin-specific protease 7 · UniProt Q9BQF6

Length
1050 aa
Mass
119.7 kDa
Annotated
2026-04-28
27 papers in source corpus 17 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SENP7 is a nucleoplasmic SUMO2/3-specific isopeptidase that deconjugates SUMO2/3 from substrates and depolymerizes poly-SUMO2/3 chains, thereby regulating chromatin organization, DNA repair, innate immunity, metabolism, and cell differentiation. Structural studies reveal that a unique Loop1 insertion in its catalytic domain forms an extended interface with SUMO2, conferring selectivity for SUMO2/3 over SUMO1 (PMID:18799455, PMID:21878624, PMID:36334780). SENP7 deSUMOylates KAP1 to promote chromatin relaxation and homologous recombination repair (PMID:24018422), deSUMOylates cGAS to activate cGAS-STING innate immune signaling (PMID:28095500), deSUMOylates PTEN in CD8+ T cells to sustain glycolysis and antitumor immunity (PMID:35143421), deSUMOylates Fli-I to drive sarcomere gene transcription in muscle (PMID:36417853), and deSUMOylates Plin4 to enable lipid droplet maturation in adipocytes (PMID:38677512). SENP7 protein abundance is controlled by SPOP- and SIAH2-mediated ubiquitin-proteasomal degradation, linking its activity to senescence and inflammatory signaling (PMID:26527005, PMID:31825833).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2008 High

    Determining the structural basis of SENP7 catalysis established that SENP7 possesses unique structural elements relative to SENP1/SENP2 that confer preferential activity toward poly-SUMO2/3 chain deconjugation rather than SUMO precursor processing.

    Evidence 2.4 Å crystal structure of the SENP7 catalytic domain combined with in vitro deconjugation assays and structure-guided mutagenesis

    PMID:18799455

    Open questions at the time
    • No enzyme–substrate co-crystal structure yet
    • Full-length protein structure and regulation unknown
    • In vivo substrates unidentified
  2. 2009 High

    Confirming SENP7's in vivo function as a poly-SUMO2/3 chain editor showed it is nucleoplasmic and that its depletion causes accumulation of high-molecular-mass SUMO2/3 conjugates and PML body alterations.

    Evidence siRNA knockdown with subcellular fractionation and immunofluorescence; in vitro assays against poly-SUMO1 vs. poly-SUMO2 substrates

    PMID:19392659

    Open questions at the time
    • Specific endogenous substrates not identified
    • PML body phenotype mechanism not dissected
  3. 2011 High

    Identifying Loop1 as the structural determinant of SUMO2/3 isoform selectivity resolved why SENP6/SENP7 discriminate between SUMO paralogs, as mutagenesis on both enzyme and SUMO surfaces swapped specificity.

    Evidence Structure-guided mutagenesis of Loop1 and SUMO surface residues with in vitro activity assays

    PMID:21878624

    Open questions at the time
    • Structural basis visualized only indirectly; enzyme–SUMO2 co-crystal awaited until 2022
    • No in vivo validation of specificity swap
  4. 2013 High

    Establishing KAP1 as a direct SENP7 substrate linked SUMO2/3 deconjugation to chromatin relaxation at DNA damage sites and homologous recombination repair, providing the first defined biological pathway for SENP7.

    Evidence Reciprocal Co-IP of SENP7–HP1α–KAP1 complex, siRNA knockdown with HR repair and DNA damage sensitivity assays, chromatin fractionation

    PMID:24018422

    Open questions at the time
    • Direct in vitro deSUMOylation of KAP1 by SENP7 not reconstituted
    • Contribution relative to SENP6 unclear
  5. 2015 High

    Multiple discoveries in 2015 expanded SENP7's roles: its tandem HP1-interaction motifs lock HP1 at pericentric heterochromatin to maintain heterochromatin integrity, SPOP-mediated ubiquitin-proteasomal degradation controls SENP7 abundance with consequences for cellular senescence, and SENP7 depletion increases c-Myc SUMOylation linking it to RNF4-dependent degradation.

    Evidence FRAP and live imaging for HP1 dynamics (PMID:25660026); Co-IP and ubiquitination assays for SPOP–SENP7 (PMID:26527005); siRNA knockdown with mass spectrometry for c-Myc SUMOylation (PMID:25895136)

    PMID:25660026 PMID:25895136 PMID:26527005

    Open questions at the time
    • c-Myc deSUMOylation by SENP7 not reconstituted in vitro
    • SPOP-SENP7 degradation not validated in vivo
    • How SENP7's catalytic and HP1-binding activities are coordinated is unknown
  6. 2017 High

    Identification of cGAS as a direct SENP7 substrate demonstrated that SENP7-mediated deSUMOylation at specific cGAS lysines relieves SUMOylation-imposed suppression of DNA sensing, oligomerization, and nucleotidyltransferase activity, placing SENP7 as a positive regulator of innate immunity.

    Evidence In vitro deSUMOylation assays, site-directed mutagenesis of cGAS K335/K372/K382, Co-IP, cGAMP activity assays, HSV-1 infection in mice

    PMID:28095500

    Open questions at the time
    • Stimulus-dependent regulation of SENP7 toward cGAS not defined
    • Relative contribution of individual SUMO sites to pathway activation in vivo unclear
  7. 2017 Medium

    Demonstrating that SENP7 is required for normal meiotic progression in oocytes extended its chromatin-regulatory roles to germ cell biology, linking SENP7 loss to histone modification changes, spindle defects, and impaired maternal-zygotic transition.

    Evidence siRNA knockdown in mouse oocytes with immunofluorescence, spindle analysis, histone modification assays, and embryo culture

    PMID:28315713

    Open questions at the time
    • Direct SENP7 substrate in oocytes not identified
    • Phenotypes observed only via knockdown without rescue
    • No conditional KO validation
  8. 2019 Medium

    Discovery that SIAH2 ubiquitinates SENP7 for proteasomal degradation in intestinal epithelial cells revealed a second E3 ligase controlling SENP7 abundance, with deregulated SENP7 promoting γδ T cell–driven intestinal inflammation.

    Evidence Co-IP and ubiquitination assays for SIAH2–SENP7, in vivo siRNA, γδ T cell depletion, DSS colitis model

    PMID:31825833

    Open questions at the time
    • SENP7 substrate responsible for γδ T cell expansion not identified
    • Whether SIAH2 and SPOP target overlapping SENP7 pools is unknown
  9. 2022 High

    Three studies in 2022 provided the SENP7–SUMO2 co-crystal structure confirming the Loop1–SUMO2 interface, identified PTEN deSUMOylation in CD8+ T cells as essential for metabolic fitness and antitumor immunity, and identified Fli-I deSUMOylation as a driver of muscle sarcomere gene transcription.

    Evidence Crystal structure of SENP7–SUMO2 complex (PMID:36334780); conditional KO with metabolic assays and PTEN deSUMOylation (PMID:35143421); SENP7 KD/KO with ChIP, Co-IP, muscle contraction assays (PMID:36417853)

    PMID:35143421 PMID:36334780 PMID:36417853

    Open questions at the time
    • How ROS triggers SENP7 cytosolic translocation is mechanistically undefined
    • Whether Fli-I deSUMOylation is direct or indirect not fully reconstituted in vitro
    • No full-length SENP7 structure available
  10. 2024 High

    Identification of Plin4 as a SENP7 substrate in adipocytes established a role for SENP7 in lipid droplet maturation, as adipocyte-specific Senp7 KO mice have smaller lipid droplets and reduced white adipose mass.

    Evidence Conventional and adipocyte-specific Senp7 KO mice, deSUMOylation assays, Plin4 localization analysis

    PMID:38677512

    Open questions at the time
    • SUMO sites on Plin4 not mapped
    • Whether other perilipins are SENP7 substrates is untested
  11. 2025 Medium

    Extension of the cGAS-STING axis to microglia and identification of IFI204 as an additional SENP7 substrate broadened the innate immune roles of SENP7, linking its deSUMOylation activity to microglial pyroptosis and neuronal apoptosis.

    Evidence Co-IP and SUMOylation assays in microglial cell lines, siRNA knockdown, Western blot

    PMID:39999677 PMID:40407969

    Open questions at the time
    • IFI204 deSUMOylation not reconstituted in vitro with purified proteins
    • In vivo neurological phenotype not validated in KO animals
    • Relative contributions of cGAS vs. IFI204 deSUMOylation to microglial pyroptosis unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the full-length structure and auto-regulatory mechanism of SENP7, the stimulus-dependent signals controlling its nucleocytoplasmic translocation, the basis for substrate selectivity among its growing list of targets, and whether SENP7 plays non-catalytic scaffold roles via its HP1-binding module independent of isopeptidase activity.
  • No full-length structure or cryo-EM model
  • Mechanism of ROS-triggered cytosolic translocation undefined
  • No systematic substrate profiling (e.g., SUMO proteomics in SENP7 KO)
  • Non-catalytic functions of HP1-binding module not separated from catalytic roles in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016787 hydrolase activity 4
Localization
GO:0005694 chromosome 2 GO:0005654 nucleoplasm 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 9 R-HSA-168256 Immune System 5 R-HSA-4839726 Chromatin organization 3 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 1 R-HSA-73894 DNA Repair 1
Partners
CGASFLI-IHP1ΑKAP1PLIN4PTENSIAH2SPOP

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Crystal structure of the SENP7 catalytic domain (2.4 Å) revealed unique structural elements compared to SENP1/SENP2; biochemical assays showed SENP7 preferentially deconjugates SUMO2/3 (including di- and poly-SUMO2/3 chains) with rates comparable to SENP2, but has lower activity for processing pre-SUMO precursors; structure-guided mutagenesis identified elements unique to the SENP6/SENP7 subclass essential for poly-SUMO chain deconjugation. X-ray crystallography (2.4 Å), in vitro biochemical deconjugation assays, structure-guided mutagenesis The Journal of biological chemistry High 18799455
2009 SENP7 is a SUMO-2/3-specific isopeptidase that cannot process SUMO precursors; its catalytic domain efficiently depolymerizes poly-SUMO2 chains but has undetectable activity against poly-SUMO1 chains; SENP7 displays isopeptidase activity against di-SUMO2 and SUMO2-modified RanGAP1 but limited activity against SUMO1-modified RanGAP1; in vivo, full-length SENP7 localizes to the nucleoplasm and preferentially reduces high-molecular-mass SUMO2/3 conjugates; siRNA-mediated depletion causes accumulation of high-molecular-mass SUMO2 species and accumulation of PML in subnuclear bodies. In vitro biochemical assays with SUMO substrates, siRNA knockdown, subcellular fractionation, immunofluorescence The Biochemical journal High 19392659
2011 A unique Loop 1 sequence insertion in SENP6/SENP7 forms a more extensive interface with SUMO during proteolysis and is essential for proteolytic activity and SUMO2/3 isoform specificity; double point mutagenesis on the SUMO surface can swap SENP6/SENP7 specificity between SUMO1 and SUMO2/3 isoforms, defining the structural determinant of isoform preference. Structural comparison, in vitro biochemical assays, site-directed mutagenesis on both SENP7 and SUMO surfaces The Journal of biological chemistry High 21878624
2013 SENP7 interacts with the chromatin repressor KAP1 through HP1α; SENP7 promotes removal of SUMO2/3 from KAP1, regulates the interaction of chromatin remodeler CHD3 with chromatin, and is required for chromatin relaxation at DNA damage sites, homologous recombination repair, and cellular resistance to DNA-damaging agents. Co-immunoprecipitation, siRNA knockdown, chromatin fractionation, HR repair assays, DNA damage sensitivity assays EMBO reports High 24018422
2015 SENP7 contains a module of two consecutive HP1-interaction motifs that restricts HP1 mobility at pericentric heterochromatin; loss of SENP7 leads to increased time spent in mitosis; SENP7's HP1-interaction module locks contiguous HP1 molecules already docked on H3K9me3-modified nucleosomes, acting on top of H3K9me3 to maintain HP1 enrichment at pericentric domains. FRAP (fluorescence recovery after photobleaching), live-cell imaging, siRNA knockdown, domain deletion/mutation analysis, mitosis timing assays Cell reports High 25660026
2015 SPOP E3 ubiquitin ligase adaptor targets SENP7 for ubiquitin-mediated proteasomal degradation; SPOP-mediated SENP7 degradation promotes cellular senescence by increasing HP1α SUMOylation, driving epigenetic gene silencing and HP1α subcellular relocalization; cancer-associated SPOP mutants cannot degrade SENP7 or drive senescence. Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, ectopic overexpression, senescence assays, immunofluorescence Cell reports High 26527005
2015 SENP7 knockdown increases SUMOylation of c-Myc, indicating SENP7 acts as a SUMO protease that regulates multi-SUMOylated c-Myc in addition to poly-SUMOylated proteins; SUMOylated c-Myc is targeted for ubiquitination and proteasomal degradation via RNF4. siRNA knockdown, mass spectrometry identification of SUMO acceptor lysines, immunoprecipitation Cell cycle (Georgetown, Tex.) Medium 25895136
2017 SENP7 directly interacts with cGAS and catalyzes its deSUMOylation; SUMO is conjugated to cGAS at lysines 335, 372, and 382, suppressing its DNA-binding, oligomerization, and nucleotidyltransferase activities; SENP7-mediated deSUMOylation relieves this inhibition to potentiate cGAS activation and downstream STING/IRF3 signaling. Co-immunoprecipitation, in vitro SUMOylation/deSUMOylation assays, site-directed mutagenesis of cGAS lysines, cGAMP activity assays, siRNA knockdown, in vivo mouse model (HSV-1 infection) PLoS pathogens High 28095500
2017 SENP7 is required for normal meiotic progression in mouse oocytes; SENP7 depletion causes meiotic arrest at prophase I and metaphase I through histone H3 hyperacetylation/hypomethylation, Cdc14B/C upregulation, CyclinB1/2 downregulation, spindle assembly defects (including γ-tubulin mislocalization and proteasomal degradation), and HP1α euchromatic deposition that restricts Rad51C loading at DNA lesions; SENP7-depleted embryos show defective maternal-zygotic transition. siRNA knockdown in mouse oocytes, immunofluorescence, spindle assembly checkpoint analysis, histone modification assays, embryo culture Biochimica et biophysica acta. Molecular cell research Medium 28315713
2019 In steady state, SENP7 expression in intestinal epithelial cells is negatively regulated by direct interaction with and ubiquitination by SIAH2 E3 ligase; upregulated epithelial SENP7 promotes expansion of proinflammatory γδ T cells driving intestinal inflammation. Co-immunoprecipitation, ubiquitination assays, siRNA knockdown in vivo, γδ T cell depletion experiments, DSS colitis model Cell reports Medium 31825833
2022 Crystal structure of human SENP7 catalytic domain bound to SUMO2 reveals that the unique Loop 1 insertion in SENP7 makes specific contacts with SUMO2 responsible for SUMO2 isoform specificity, while SUMO2 C-terminal tail contacts are conserved across the SENP/ULP family. X-ray crystallography of SENP7–SUMO2 complex, structural comparison Journal of molecular biology High 36334780
2022 ROS-triggered cytosolic translocation of SENP7 in CD8+ T cells mediates PTEN deSUMOylation, promoting PTEN degradation and preventing PTEN-dependent metabolic defects; SENP7 deficiency leads to decreased glycolysis and oxidative phosphorylation, reduced proliferation, and dampened antitumor functions. Conditional KO mice, metabolic assays (glycolysis/OXPHOS), immunoprecipitation for PTEN deSUMOylation, subcellular fractionation showing cytosolic SENP7 translocation, in vivo tumor models The Journal of clinical investigation High 35143421
2022 SENP7 deSUMOylates flightless-1 (Fli-I), promoting its association with scaffold attachment factor b1 (Safb1); SENP7 deficiency leads to higher Fli-I SUMOylation, lower Safb1 chromatin residency, transcriptionally incompetent chromatin at the MyHC-IId gene locus, reduced MyHC-IId expression, sarcomere disorganization, and impaired muscle cell contraction; cachexia signaling impedes this SENP7-governed program. SENP7 KD/KO, chromatin immunoprecipitation, Co-immunoprecipitation (Fli-I/Safb1), SUMOylation assays, muscle contraction assays, sarcomere morphology analysis Cell reports High 36417853
2024 Senp7 deSUMOylates the perilipin family protein Plin4, promoting Plin4 localization to lipid droplets; Senp7-deficient adipocytes have significantly smaller lipid droplets and reduced white adipose tissue mass, indicating Senp7 is required for lipid droplet maturation. Conventional and adipocyte-specific Senp7 KO mice, deSUMOylation assays, lipid droplet morphology analysis, subcellular localization of Plin4 The Journal of biological chemistry High 38677512
2026 SENP7 promotes regulatory B-cell (Breg) differentiation and inhibits senescence by activating SIRT1 expression via deSUMOylation; this SENP7-SIRT1 axis enhances IL-10 expression and immune evasion in colorectal cancer. Co-immunoprecipitation, primary mouse cell sorting, adoptive transfer experiments, flow cytometry International journal of biological sciences Medium 41362746
2025 In microglia, SENP7 interacts with IFI204, catalyzes its deSUMOylation, and promotes STING signal activation, driving microglial pyroptosis and mitochondrial dysfunction; SENP7-mediated deSUMOylation of cGAS activates the cGAS/STING/IRF3 pathway, triggering microglial pyroptosis and subsequent neuronal apoptosis. Co-immunoprecipitation, immunoprecipitation SUMOylation assay, Western blot, siRNA knockdown Cytokine / Cell biology and toxicology Medium 39999677 40407969

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Structure of the human SENP7 catalytic domain and poly-SUMO deconjugation activities for SENP6 and SENP7. The Journal of biological chemistry 118 18799455
2017 SENP7 Potentiates cGAS Activation by Relieving SUMO-Mediated Inhibition of Cytosolic DNA Sensing. PLoS pathogens 111 28095500
2009 Characterization of SENP7, a SUMO-2/3-specific isopeptidase. The Biochemical journal 94 19392659
2013 The deSUMOylase SENP7 promotes chromatin relaxation for homologous recombination DNA repair. EMBO reports 92 24018422
2015 c-Myc is targeted to the proteasome for degradation in a SUMOylation-dependent manner, regulated by PIAS1, SENP7 and RNF4. Cell cycle (Georgetown, Tex.) 87 25895136
2022 SENP7 senses oxidative stress to sustain metabolic fitness and antitumor functions of CD8+ T cells. The Journal of clinical investigation 65 35143421
2015 SPOP E3 Ubiquitin Ligase Adaptor Promotes Cellular Senescence by Degrading the SENP7 deSUMOylase. Cell reports 63 26527005
2015 The SENP7 SUMO-Protease Presents a Module of Two HP1 Interaction Motifs that Locks HP1 Protein at Pericentric Heterochromatin. Cell reports 45 25660026
2017 Maternal SENP7 programs meiosis architecture and embryo survival in mouse. Biochimica et biophysica acta. Molecular cell research 35 28315713
2011 Swapping small ubiquitin-like modifier (SUMO) isoform specificity of SUMO proteases SENP6 and SENP7. The Journal of biological chemistry 32 21878624
2019 DeSUMOylase SENP7-Mediated Epithelial Signaling Triggers Intestinal Inflammation via Expansion of Gamma-Delta T Cells. Cell reports 27 31825833
2016 The Sumo protease Senp7 is required for proper neuronal differentiation. Biochimica et biophysica acta 23 27039038
2020 SENP7 knockdown inhibited pyroptosis and NF-κB/NLRP3 inflammasome pathway activation in Raw 264.7 cells. Scientific reports 15 33004957
2024 Senp7 deficiency impairs lipid droplets maturation in white adipose tissues via Plin4 deSUMOylation. The Journal of biological chemistry 11 38677512
2022 Structural Basis for the SUMO2 Isoform Specificity of SENP7. Journal of molecular biology 11 36334780
2022 SENP7 deSUMOylase-governed transcriptional program coordinates sarcomere assembly and is targeted in muscle atrophy. Cell reports 10 36417853
2023 Exome sequencing links the SUMO protease SENP7 with fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia. Journal of medical genetics 6 37460201
2025 IFI204 in microglia mediates traumatic brain injury-induced mitochondrial dysfunction and pyroptosis via SENP7 interaction. Cell biology and toxicology 4 40407969
2025 Microglial pyroptosis induced by SENP7 via the cGAS/STING/IRF3 pathway contributes to neuronal apoptosis. Cytokine 3 39999677
2024 Biallelic Loss of Function Variants in SENP7 Cause Immunodeficiency with Neurologic and Muscular Phenotypes. The Journal of pediatrics 3 38972567
2026 A SENP7-SIRT1-IL-10 Axis Driven by DeSUMOylation Promotes Breg Differentiation and Immune Evasion in Colorectal Cancer. International journal of biological sciences 2 41362746
2025 A Splice Site Variant in SENP7 Results in a Severe Form of Arthrogryposis. Clinical genetics 1 39754459
2025 Lethal Phenotype and Expansion of the Clinical Spectrum of Biallelic Loss of Function Variant in SENP7 Gene Unveiled by Whole Exome Sequencing. Clinical genetics 1 39763084
2025 Aging impairs the antiviral defense in Caenorhabditis elegans due to loss of DRH-1/RIG-I deSUMOylation by ULP-4/SENP7. EMBO reports 1 41039133
2024 SENP7 inhibits glioblastoma metastasis and invasion by dissociating SUMO2/3 binding to specific target proteins. Open medicine (Warsaw, Poland) 1 39381427
2025 Identification of SENP7 and UTF1/VENTX as new loci influencing clustered protocadherin methylation across blood and brain using a genome-wide association study. Molecular psychiatry 0 41039089
2024 Antiviral defense in aged Caenorhabditis elegans declines due to loss of DRH-1/RIG-I deSUMOylation via ULP-4/SENP7. bioRxiv : the preprint server for biology 0 39605404