{"gene":"SENP7","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2008,"finding":"Crystal structure of the SENP7 catalytic domain (2.4 Å) revealed unique structural elements compared to SENP1/SENP2. Biochemical assays showed SENP7 prefers SUMO2/SUMO3 for deconjugation, with rates comparable to SENP2 for di-SUMO2, di-SUMO3, and poly-SUMO2/3 chains, but exhibits lower rates for processing pre-SUMO1/2/3. Structure-guided mutagenesis identified elements unique to the SENP6/SENP7 subclass that contribute to poly-SUMO chain deconjugation.","method":"X-ray crystallography (2.4 Å), in vitro biochemical deconjugation assays, structure-guided mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with in vitro enzymatic assays and mutagenesis in a single rigorous study","pmids":["18799455"],"is_preprint":false},{"year":2009,"finding":"SENP7 C-terminal catalytic domain efficiently depolymerizes poly-SUMO2 chains but has undetectable activity against poly-SUMO1 chains. It shows 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 knockdown leads to accumulation of high-molecular-mass SUMO2 species and accumulation of PML in subnuclear bodies.","method":"In vitro isopeptidase assays, siRNA knockdown, subcellular fractionation/localization, immunofluorescence","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (in vitro assay, cellular localization, KD phenotype) replicated key findings from concurrent structural work","pmids":["19392659"],"is_preprint":false},{"year":2011,"finding":"A unique sequence insertion (Loop 1) in the SENP6/SENP7 subclass is essential for their proteolytic activity and forms a more extensive interface with SUMO during the proteolytic reaction. Double point mutations on the SUMO surface swap the SUMO2/3 isoform specificity of SENP6 and SENP7 toward SUMO1, identifying the structural basis for SUMO2/3 preference.","method":"Structure-based mutagenesis, in vitro biochemical assays, structural comparison","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with biochemical activity assays in a single study demonstrating mechanistic determinants of isoform specificity","pmids":["21878624"],"is_preprint":false},{"year":2013,"finding":"SENP7 interacts with KAP1 through HP1α, promotes removal of SUMO2/3 from KAP1, and regulates interaction of chromatin remodeler CHD3 with chromatin. SENP7 is required for chromatin relaxation in response to DNA damage, for homologous recombination repair, and for cellular resistance to DNA-damaging agents.","method":"Co-immunoprecipitation, siRNA knockdown, chromatin immunoprecipitation, HR repair assays, DNA damage sensitivity assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP establishing binding partners, combined with functional KD phenotypes showing pathway placement in HR repair","pmids":["24018422"],"is_preprint":false},{"year":2015,"finding":"SENP7 contains a module of two consecutive HP1 interaction motifs that lock HP1 at pericentric heterochromatin by restricting HP1 mobility. Loss of SENP7 leads to increased time spent in mitosis and reduced HP1 enrichment at pericentric domains. This locking mechanism acts on top of H3K9me3 to maintain HP1 enrichment.","method":"Live-cell imaging (FRAP), siRNA knockdown, immunofluorescence, time-lapse microscopy, mutational analysis of HP1-interaction motifs","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — FRAP and live imaging directly showing HP1 mobility restriction, combined with mutagenesis of HP1 interaction motifs and mitotic phenotype","pmids":["25660026"],"is_preprint":false},{"year":2015,"finding":"SPOP E3 ubiquitin ligase adaptor targets SENP7 for ubiquitin-mediated proteasomal degradation. SPOP-mediated degradation of SENP7 promotes cellular senescence by increasing HP1α SUMOylation, leading to HP1α subcellular re-localization and epigenetic gene silencing. Cancer-associated SPOP mutants fail to degrade SENP7.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, ectopic expression of wild-type and mutant SPOP, immunofluorescence, senescence assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, and functional phenotype (senescence) in single study with multiple orthogonal approaches","pmids":["26527005"],"is_preprint":false},{"year":2015,"finding":"c-Myc is a substrate for SENP7-regulated deSUMOylation. Knockdown of SENP7 increased c-Myc SUMOylation, indicating SENP7 deconjugates SUMO from c-Myc. SUMOylated c-Myc is subsequently ubiquitylated by RNF4 and degraded by the proteasome.","method":"siRNA knockdown, mass spectrometry to identify SUMO acceptor lysines, SUMOylation assays","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA KD showing increased c-Myc SUMOylation, with mass spectrometry identifying modification sites, but no direct reconstitution of SENP7 activity on c-Myc","pmids":["25895136"],"is_preprint":false},{"year":2017,"finding":"SENP7 interacts with cGAS and catalyzes its deSUMOylation. SUMO is conjugated to cGAS at lysine residues K335, K372, and K382, which suppresses cGAS DNA-binding, oligomerization, and nucleotidyl-transferase activities. SENP7-mediated deSUMOylation of cGAS relieves this inhibition. SENP7 knockdown markedly impaired IRF3-responsive gene expression induced by the cGAS-STING axis.","method":"Co-immunoprecipitation, site-directed mutagenesis of cGAS SUMOylation sites, in vitro nucleotidyl-transferase assay, siRNA knockdown, IRF3 reporter assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including Co-IP, site-directed mutagenesis of target lysines, in vitro activity assay, and functional KD phenotype","pmids":["28095500"],"is_preprint":false},{"year":2017,"finding":"Maternal SENP7 is required for meiotic progression in mouse oocytes. SENP7-depleted oocytes showed meiotic arrest at prophase I and metaphase I, with histone H3 hyperacetylation and hypomethylation, Cdc14B/C upregulation, CyclinB1/B2 downregulation, defective spindle assembly, and mislocalization/ubiquitylation-mediated proteasomal degradation of γ-tubulin. SENP7-depleted embryos exhibited defective maternal-zygotic transition and failed to produce blastocysts.","method":"siRNA microinjection into oocytes, immunofluorescence, Western blotting, live-cell imaging, chromatin staining","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function in oocytes with specific molecular phenotypes including histone modification changes and spindle defects","pmids":["28315713"],"is_preprint":false},{"year":2019,"finding":"In steady state, SENP7 expression in intestinal epithelial cells is negatively regulated by direct interaction with and ubiquitination by SIAH2. In IBD, upregulated SENP7 displays a distinct interactome and drives expansion of proinflammatory γδ T cells. In vivo knockdown of SENP7 abrogated DSS-induced gut inflammation.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA/shRNA knockdown in vivo, flow cytometry, mouse DSS colitis model","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing SIAH2 interaction, ubiquitination assay, and in vivo knockdown with defined inflammatory phenotype","pmids":["31825833"],"is_preprint":false},{"year":2022,"finding":"SENP7 catalyzes deSUMOylation of PTEN in response to ROS (oxidative stress) in CD8+ T cells, triggering PTEN degradation and preventing PTEN-dependent metabolic defects. Oxidative stress triggers cytosolic translocation of SENP7, enabling PTEN deSUMOylation. SENP7-deficient CD8+ T cells show decreased glycolysis and oxidative phosphorylation, attenuated proliferation in vitro, and dampened antitumor functions in vivo.","method":"SENP7 conditional KO mice, metabolic assays (glycolysis, OXPHOS), Co-immunoprecipitation, subcellular fractionation, in vivo tumor models, human CRC samples","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with metabolic phenotype, Co-IP establishing PTEN interaction, subcellular fractionation showing ROS-triggered translocation, validated in human samples","pmids":["35143421"],"is_preprint":false},{"year":2022,"finding":"Crystal structure of SENP7 catalytic domain bound to SUMO2 revealed that the Loop1 insertion in SENP7 makes specific contacts with SUMO2 responsible for SUMO2 isoform specificity. Other interface contacts between SENP7 and SUMO2 (including C-terminal tail interaction) are conserved among SENP/ULP family members.","method":"X-ray crystallography, structural analysis, comparison with SENP family members","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of SENP7:SUMO2 complex with identification of specific loop contacts, in a single rigorous structural study","pmids":["36334780"],"is_preprint":false},{"year":2022,"finding":"SENP7 directly regulates transcription of the myosin heavy chain MyHC-IId gene. SENP7 deSUMOylates flightless-1 (Fli-I), signaling its association with Safb1. SENP7 deficiency leads to higher Fli-I SUMOylation, lower Safb1 chromatin residency, transcriptionally incompetent chromatin on MyHC-IId, sarcomere disorganization, and disrupted muscle cell contraction. Cachexia signaling impedes the SENP7-governed transcriptional program.","method":"SENP7 KO muscle cells, ChIP assay, Co-immunoprecipitation, SUMOylation assay, contraction assays, chromatin conformation analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches including Co-IP, SUMOylation assay, ChIP, and functional contraction phenotype establishing pathway from SENP7 to sarcomere organization","pmids":["36417853"],"is_preprint":false},{"year":2024,"finding":"SENP7 deSUMOylates perilipin family protein Plin4, promoting Plin4 localization to lipid droplets. Senp7-deficient mice (conventional and adipocyte-specific KO) display reduced white adipose tissue mass, decreased adipocyte size, and significantly smaller lipid droplets.","method":"Conditional and conventional KO mice, lipid droplet morphology analysis, SUMOylation assay, Co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two independent KO mouse models with specific lipid droplet phenotype and direct biochemical demonstration of Plin4 deSUMOylation","pmids":["38677512"],"is_preprint":false},{"year":2025,"finding":"SENP7 interacts with IFI204 in microglia, catalyzes the deSUMOylation of IFI204, and promotes STING signal activation, driving microglial pyroptosis and mitochondrial dysfunction.","method":"Co-immunoprecipitation, Western blotting, immunofluorescence, molecular docking","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP and molecular docking establishing interaction, with functional pyroptosis phenotype, but limited mechanistic depth in the abstract","pmids":["40407969"],"is_preprint":false},{"year":2025,"finding":"SENP7 facilitates activation of the cGAS/STING/IRF3 axis by regulating deSUMOylation of cGAS, triggering microglial pyroptosis that leads to neuronal apoptosis. SENP7 knockdown inhibited GSDMD-N, Caspase1, and NLRP3 protein levels and reduced IL-1β and IL-18 concentrations in LPS-ATP-stimulated BV2 cells.","method":"Immunoprecipitation SUMOylation assay, siRNA knockdown, Western blotting, co-culture assay","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — SUMOylation assay and KD phenotype corroborating prior cGAS deSUMOylation findings from PMID:28095500 in a neuroinflammatory context","pmids":["39999677"],"is_preprint":false},{"year":2026,"finding":"SENP7 promotes regulatory B-cell (Breg) differentiation by activating SIRT1 expression via deSUMOylation, thereby enhancing IL-10 gene expression and inhibiting B-cell senescence.","method":"Co-immunoprecipitation, flow cytometry, adoptive transfer experiments, primary mouse cell sorting","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP and functional experiments in a single study, limited mechanistic detail on deSUMOylation of SIRT1 in abstract","pmids":["41362746"],"is_preprint":false}],"current_model":"SENP7 is a SUMO2/3-specific isopeptidase (confirmed by crystal structure and biochemistry) whose Loop1 insertion confers SUMO2/3 isoform selectivity and poly-SUMO chain disassembly activity; it localizes predominantly to the nucleoplasm where it deSUMOylates substrates including KAP1 (enabling chromatin relaxation for homologous recombination), HP1α (controlling pericentric heterochromatin integrity and mitosis), cGAS (activating innate immune signaling), PTEN (sustaining CD8+ T cell metabolic fitness in response to oxidative stress), Fli-I (coordinating sarcomere assembly via transcriptional regulation of MyHC-IId), Plin4 (promoting lipid droplet maturation in adipocytes), and c-Myc (regulating its proteasomal degradation); SENP7 protein stability is itself controlled by SPOP-mediated ubiquitination and SIAH2-mediated ubiquitination, linking SENP7 to cellular senescence and intestinal inflammation."},"narrative":{"mechanistic_narrative":"SENP7 is a SUMO2/3-specific isopeptidase that disassembles poly-SUMO2/3 chains and removes SUMO2/3 from conjugated substrates, acting as a deSUMOylation hub that links chromatin dynamics, innate immune signaling, and cellular metabolism [PMID:18799455, PMID:19392659]. Crystallographic and biochemical work established that SENP7 strongly prefers SUMO2/3 over SUMO1, with rates comparable to SENP2 against di- and poly-SUMO2/3, and that a unique Loop1 insertion in the SENP6/SENP7 subclass forms an extensive interface with SUMO2 that confers isoform selectivity and supports poly-SUMO chain deconjugation [PMID:18799455, PMID:21878624, PMID:36334780]. The full-length enzyme localizes predominantly to the nucleoplasm, where its depletion causes accumulation of high-molecular-mass SUMO2/3 conjugates [PMID:19392659]. In chromatin, SENP7 is recruited through HP1α to deSUMOylate KAP1, controlling CHD3 association and enabling chromatin relaxation required for homologous recombination and resistance to DNA-damaging agents [PMID:24018422]; a tandem HP1-interaction module additionally locks HP1 at pericentric heterochromatin to maintain its enrichment and proper mitotic progression [PMID:25660026]. SENP7 deSUMOylates a broad substrate set that defines distinct cellular roles: cGAS, where SUMO removal relieves inhibition of DNA-binding and nucleotidyl-transferase activity to drive cGAS-STING/IRF3 innate immune output [PMID:28095500]; PTEN, where ROS-triggered cytosolic translocation of SENP7 permits PTEN deSUMOylation, degradation, and sustained CD8+ T cell metabolic fitness and antitumor function [PMID:35143421]; the transcriptional regulator Fli-I, coordinating Safb1 chromatin residency and MyHC-IId transcription for sarcomere assembly [PMID:36417853]; and Plin4, promoting its lipid-droplet localization and adipocyte lipid droplet maturation [PMID:38677512]. SENP7 protein levels are themselves set by ubiquitin ligases: SPOP-mediated degradation restrains SENP7 to promote senescence via HP1α SUMOylation, and SIAH2-mediated ubiquitination keeps SENP7 low in intestinal epithelium, with dysregulated SENP7 driving proinflammatory γδ T-cell expansion and gut inflammation [PMID:26527005, PMID:31825833].","teleology":[{"year":2008,"claim":"Established that SENP7 is a SUMO2/3-preferring isopeptidase structurally distinct from SENP1/2, defining its catalytic identity and chain-processing capacity.","evidence":"X-ray crystallography of the catalytic domain with in vitro deconjugation assays and structure-guided mutagenesis","pmids":["18799455"],"confidence":"High","gaps":["No substrate-bound structure to explain isoform selectivity at this stage","Cellular substrates not yet identified"]},{"year":2009,"claim":"Confirmed the SUMO2/3 chain-editing function in cells, showing SENP7 controls high-molecular-mass SUMO2/3 conjugate levels in the nucleoplasm.","evidence":"In vitro isopeptidase assays, siRNA knockdown, subcellular fractionation and immunofluorescence","pmids":["19392659"],"confidence":"High","gaps":["Specific physiological substrates not defined","Mechanism of nucleoplasmic targeting unknown"]},{"year":2011,"claim":"Identified the Loop1 insertion as the structural determinant of SUMO2/3 isoform specificity, explaining why SENP6/SENP7 favor SUMO2/3.","evidence":"Structure-based mutagenesis swapping SUMO surface residues with in vitro activity assays","pmids":["21878624"],"confidence":"High","gaps":["Direct visualization of the Loop1-SUMO contacts awaited a complex structure"]},{"year":2013,"claim":"Placed SENP7 in the DNA damage response by showing HP1α-bridged deSUMOylation of KAP1 enables chromatin relaxation and homologous recombination.","evidence":"Co-IP, siRNA knockdown, ChIP, HR repair and DNA damage sensitivity assays","pmids":["24018422"],"confidence":"High","gaps":["Whether KAP1 deSUMOylation is direct or HP1α-dependent for catalysis not fully resolved"]},{"year":2015,"claim":"Revealed a non-catalytic chromatin role: tandem HP1-interaction motifs lock HP1 at pericentric heterochromatin, coupling SENP7 to mitotic fidelity.","evidence":"FRAP live-cell imaging, knockdown, mutational analysis of HP1-interaction motifs, mitotic timing","pmids":["25660026"],"confidence":"High","gaps":["Relationship between the locking function and deSUMOylase activity unclear"]},{"year":2015,"claim":"Showed SENP7 abundance is controlled by SPOP-mediated ubiquitination, linking its turnover to senescence through HP1α SUMOylation.","evidence":"Co-IP, ubiquitination assays, wild-type/mutant SPOP expression, senescence assays","pmids":["26527005"],"confidence":"High","gaps":["Generality of SPOP control across tissues not established"]},{"year":2015,"claim":"Extended SENP7 substrate range to c-Myc, positioning deSUMOylation upstream of RNF4-mediated proteasomal control of c-Myc.","evidence":"siRNA knockdown, mass spectrometry of SUMO acceptor lysines, SUMOylation assays","pmids":["25895136"],"confidence":"Medium","gaps":["No direct in vitro reconstitution of SENP7 acting on c-Myc","Functional consequence for c-Myc target genes not shown"]},{"year":2017,"claim":"Defined a positive role for SENP7 in innate immunity by deSUMOylating cGAS to relieve SUMO-mediated suppression of its catalytic and DNA-binding activities.","evidence":"Co-IP, site-directed mutagenesis of cGAS SUMO sites, in vitro nucleotidyl-transferase assay, IRF3 reporter","pmids":["28095500"],"confidence":"High","gaps":["In vivo immune consequence of SENP7 loss not addressed in this study"]},{"year":2017,"claim":"Demonstrated a maternal requirement for SENP7 in meiotic progression and the maternal-zygotic transition.","evidence":"siRNA microinjection in mouse oocytes, immunofluorescence, live imaging, chromatin staining","pmids":["28315713"],"confidence":"Medium","gaps":["Direct SUMO substrates driving meiotic phenotypes not identified","Causal link between histone modification changes and spindle defects unresolved"]},{"year":2019,"claim":"Showed SIAH2-mediated ubiquitination restrains SENP7 in intestinal epithelium, with dysregulated SENP7 driving proinflammatory γδ T-cell expansion in IBD.","evidence":"Co-IP, ubiquitination assay, in vivo knockdown, flow cytometry, DSS colitis model","pmids":["31825833"],"confidence":"Medium","gaps":["SENP7 substrates underlying the inflammatory interactome not defined","Mechanism linking epithelial SENP7 to γδ T cells incomplete"]},{"year":2022,"claim":"Linked SENP7 to T-cell metabolism by showing ROS-triggered cytosolic translocation enables PTEN deSUMOylation and degradation to sustain CD8+ T-cell fitness and antitumor activity.","evidence":"Conditional KO mice, metabolic assays, Co-IP, subcellular fractionation, tumor models, human CRC samples","pmids":["35143421"],"confidence":"High","gaps":["Signal that triggers SENP7 cytosolic translocation upon ROS not defined","Whether nuclear functions are concurrently affected unclear"]},{"year":2022,"claim":"Provided the SENP7:SUMO2 co-crystal structure, directly visualizing Loop1 contacts that explain SUMO2 isoform specificity.","evidence":"X-ray crystallography of the catalytic domain bound to SUMO2 with family comparison","pmids":["36334780"],"confidence":"High","gaps":["No structure with a physiological poly-SUMO substrate"]},{"year":2022,"claim":"Established a transcriptional/sarcomere role: SENP7 deSUMOylates Fli-I to promote Safb1 chromatin residency and MyHC-IId transcription for muscle contraction.","evidence":"SENP7 KO muscle cells, ChIP, Co-IP, SUMOylation assay, contraction and chromatin conformation analyses","pmids":["36417853"],"confidence":"High","gaps":["How cachexia signaling impedes the SENP7 program mechanistically unresolved"]},{"year":2024,"claim":"Showed SENP7 deSUMOylates Plin4 to drive its lipid-droplet localization, defining a role in adipocyte lipid droplet maturation.","evidence":"Conventional and adipocyte-specific KO mice, lipid droplet morphology, SUMOylation assay, Co-IP","pmids":["38677512"],"confidence":"High","gaps":["Whether SENP7 acts at the lipid droplet itself or upstream in the cytosol not defined"]},{"year":2025,"claim":"Implicated SENP7-driven deSUMOylation of cGAS and IFI204 in microglial STING activation and pyroptosis in neuroinflammation.","evidence":"Co-IP, SUMOylation assays, siRNA knockdown, molecular docking, co-culture in BV2/microglial models","pmids":["40407969","39999677"],"confidence":"Medium","gaps":["IFI204 interaction relies partly on docking without structural validation","Limited mechanistic depth on deSUMOylation kinetics in these contexts"]},{"year":2026,"claim":"Extended SENP7 function to regulatory B-cell biology via deSUMOylation-dependent activation of SIRT1 and IL-10 expression.","evidence":"Co-IP, flow cytometry, adoptive transfer, primary cell sorting","pmids":["41362746"],"confidence":"Medium","gaps":["Direct deSUMOylation of SIRT1 not biochemically reconstituted","SIRT1 SUMO sites not mapped"]},{"year":null,"claim":"How SENP7 substrate selection and subcellular partitioning are coordinated across its diverse roles (chromatin, immunity, metabolism) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for context-specific substrate recognition","Regulators governing nuclear vs cytosolic localization beyond ROS not defined","No structure of SENP7 engaging a full-length physiological substrate"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,7,10,12,13]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,2,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,10,6]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,9,15]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["KAP1","HP1Α","CHD3","CGAS","PTEN","FLI-I","PLIN4","SPOP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BQF6","full_name":"Sentrin-specific protease 7","aliases":["SUMO-1-specific protease 2","Sentrin/SUMO-specific protease SENP7"],"length_aa":1050,"mass_kda":119.7,"function":"Protease that acts as a positive regulator of the cGAS-STING pathway by catalyzing desumoylation of CGAS. Desumoylation of CGAS promotes DNA-binding activity of CGAS, subsequent oligomerization and activation (By similarity). Deconjugates SUMO2 and SUMO3 from targeted proteins, but not SUMO1 (PubMed:18799455). Catalyzes the deconjugation of poly-SUMO2 and poly-SUMO3 chains (PubMed:18799455). Has very low efficiency in processing full-length SUMO proteins to their mature forms (PubMed:18799455)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9BQF6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SENP7","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SENP7","total_profiled":1310},"omim":[{"mim_id":"612846","title":"SENTRIN-SPECIFIC PROTEASE FAMILY, MEMBER 7; SENP7","url":"https://www.omim.org/entry/612846"},{"mim_id":"605003","title":"SENTRIN-SPECIFIC PROTEASE FAMILY, MEMBER 6; SENP6","url":"https://www.omim.org/entry/605003"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SENP7"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9BQF6","domains":[{"cath_id":"-","chopping":"715-743","consensus_level":"medium","plddt":48.1007,"start":715,"end":743},{"cath_id":"3.30.310.130","chopping":"748-816_827-879_928-1049","consensus_level":"high","plddt":92.3419,"start":748,"end":1049},{"cath_id":"2.30.29","chopping":"520-682","consensus_level":"high","plddt":80.4956,"start":520,"end":682}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BQF6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BQF6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BQF6-F1-predicted_aligned_error_v6.png","plddt_mean":56.09},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SENP7","jax_strain_url":"https://www.jax.org/strain/search?query=SENP7"},"sequence":{"accession":"Q9BQF6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BQF6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BQF6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BQF6"}},"corpus_meta":[{"pmid":"18799455","id":"PMC_18799455","title":"Structure of the human SENP7 catalytic domain and poly-SUMO deconjugation activities for SENP6 and SENP7.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18799455","citation_count":118,"is_preprint":false},{"pmid":"28095500","id":"PMC_28095500","title":"SENP7 Potentiates cGAS Activation by Relieving SUMO-Mediated Inhibition of Cytosolic DNA Sensing.","date":"2017","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/28095500","citation_count":113,"is_preprint":false},{"pmid":"19392659","id":"PMC_19392659","title":"Characterization of SENP7, a SUMO-2/3-specific isopeptidase.","date":"2009","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/19392659","citation_count":94,"is_preprint":false},{"pmid":"24018422","id":"PMC_24018422","title":"The deSUMOylase SENP7 promotes chromatin relaxation for homologous recombination DNA repair.","date":"2013","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/24018422","citation_count":92,"is_preprint":false},{"pmid":"25895136","id":"PMC_25895136","title":"c-Myc is targeted to the proteasome for degradation in a SUMOylation-dependent manner, regulated by PIAS1, SENP7 and RNF4.","date":"2015","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/25895136","citation_count":88,"is_preprint":false},{"pmid":"35143421","id":"PMC_35143421","title":"SENP7 senses oxidative stress to sustain metabolic fitness and antitumor functions of CD8+ T cells.","date":"2022","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/35143421","citation_count":66,"is_preprint":false},{"pmid":"26527005","id":"PMC_26527005","title":"SPOP E3 Ubiquitin Ligase Adaptor Promotes Cellular Senescence by Degrading the SENP7 deSUMOylase.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26527005","citation_count":63,"is_preprint":false},{"pmid":"25660026","id":"PMC_25660026","title":"The SENP7 SUMO-Protease Presents a Module of Two HP1 Interaction Motifs that Locks HP1 Protein at Pericentric Heterochromatin.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25660026","citation_count":45,"is_preprint":false},{"pmid":"28315713","id":"PMC_28315713","title":"Maternal SENP7 programs meiosis architecture and embryo survival in mouse.","date":"2017","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/28315713","citation_count":35,"is_preprint":false},{"pmid":"21878624","id":"PMC_21878624","title":"Swapping small ubiquitin-like modifier (SUMO) isoform specificity of SUMO proteases SENP6 and SENP7.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21878624","citation_count":32,"is_preprint":false},{"pmid":"31825833","id":"PMC_31825833","title":"DeSUMOylase SENP7-Mediated Epithelial Signaling Triggers Intestinal Inflammation via Expansion of Gamma-Delta T Cells.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31825833","citation_count":27,"is_preprint":false},{"pmid":"27039038","id":"PMC_27039038","title":"The Sumo protease Senp7 is required for proper neuronal differentiation.","date":"2016","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/27039038","citation_count":23,"is_preprint":false},{"pmid":"33004957","id":"PMC_33004957","title":"SENP7 knockdown inhibited pyroptosis and NF-κB/NLRP3 inflammasome pathway activation in Raw 264.7 cells.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33004957","citation_count":15,"is_preprint":false},{"pmid":"38677512","id":"PMC_38677512","title":"Senp7 deficiency impairs lipid droplets maturation in white adipose tissues via Plin4 deSUMOylation.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38677512","citation_count":13,"is_preprint":false},{"pmid":"36334780","id":"PMC_36334780","title":"Structural Basis for the SUMO2 Isoform Specificity of SENP7.","date":"2022","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36334780","citation_count":11,"is_preprint":false},{"pmid":"36417853","id":"PMC_36417853","title":"SENP7 deSUMOylase-governed transcriptional program coordinates sarcomere assembly and is targeted in muscle atrophy.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36417853","citation_count":10,"is_preprint":false},{"pmid":"37460201","id":"PMC_37460201","title":"Exome sequencing links the SUMO protease SENP7 with fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia.","date":"2023","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37460201","citation_count":6,"is_preprint":false},{"pmid":"40407969","id":"PMC_40407969","title":"IFI204 in microglia mediates traumatic brain injury-induced mitochondrial dysfunction and pyroptosis via SENP7 interaction.","date":"2025","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/40407969","citation_count":5,"is_preprint":false},{"pmid":"39999677","id":"PMC_39999677","title":"Microglial pyroptosis induced by SENP7 via the cGAS/STING/IRF3 pathway contributes to neuronal apoptosis.","date":"2025","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/39999677","citation_count":4,"is_preprint":false},{"pmid":"41362746","id":"PMC_41362746","title":"A SENP7-SIRT1-IL-10 Axis Driven by DeSUMOylation Promotes Breg Differentiation and Immune Evasion in Colorectal Cancer.","date":"2026","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41362746","citation_count":3,"is_preprint":false},{"pmid":"38972567","id":"PMC_38972567","title":"Biallelic Loss of Function Variants in SENP7 Cause Immunodeficiency with Neurologic and Muscular Phenotypes.","date":"2024","source":"The Journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/38972567","citation_count":3,"is_preprint":false},{"pmid":"39381427","id":"PMC_39381427","title":"SENP7 inhibits glioblastoma metastasis and invasion by dissociating SUMO2/3 binding to specific target proteins.","date":"2024","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/39381427","citation_count":1,"is_preprint":false},{"pmid":"41039133","id":"PMC_41039133","title":"Aging impairs the antiviral defense in Caenorhabditis elegans due to loss of DRH-1/RIG-I deSUMOylation by ULP-4/SENP7.","date":"2025","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/41039133","citation_count":1,"is_preprint":false},{"pmid":"39763084","id":"PMC_39763084","title":"Lethal Phenotype and Expansion of the Clinical Spectrum of Biallelic Loss of Function Variant in SENP7 Gene Unveiled by Whole Exome Sequencing.","date":"2025","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39763084","citation_count":1,"is_preprint":false},{"pmid":"39754459","id":"PMC_39754459","title":"A Splice Site Variant in SENP7 Results in a Severe Form of Arthrogryposis.","date":"2025","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39754459","citation_count":1,"is_preprint":false},{"pmid":"39605404","id":"PMC_39605404","title":"Antiviral defense in aged Caenorhabditis elegans declines due to loss of DRH-1/RIG-I deSUMOylation via ULP-4/SENP7.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39605404","citation_count":0,"is_preprint":false},{"pmid":"41039089","id":"PMC_41039089","title":"Identification of SENP7 and UTF1/VENTX as new loci influencing clustered protocadherin methylation across blood and brain using a genome-wide association study.","date":"2025","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/41039089","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.12.623310","title":"Antiviral defense in aged  <i>Caenorhabditis elegans</i>  declines due to loss of DRH-1/RIG-I deSUMOylation via ULP-4/SENP7","date":"2024-11-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.12.623310","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.19.629385","title":"Identification of  <i>SENP7</i>  and  <i>UTF1</i>  /  <i>VENTX</i>  as new loci influencing clustered protocadherin methylation across blood and brain using a genome-wide association study","date":"2024-12-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.19.629385","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15519,"output_tokens":4671,"usd":0.058311,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12706,"output_tokens":4813,"usd":0.091927,"stage2_stop_reason":"end_turn"},"total_usd":0.150238,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structure of the SENP7 catalytic domain (2.4 Å) revealed unique structural elements compared to SENP1/SENP2. Biochemical assays showed SENP7 prefers SUMO2/SUMO3 for deconjugation, with rates comparable to SENP2 for di-SUMO2, di-SUMO3, and poly-SUMO2/3 chains, but exhibits lower rates for processing pre-SUMO1/2/3. Structure-guided mutagenesis identified elements unique to the SENP6/SENP7 subclass that contribute to poly-SUMO chain deconjugation.\",\n      \"method\": \"X-ray crystallography (2.4 Å), in vitro biochemical deconjugation assays, structure-guided mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with in vitro enzymatic assays and mutagenesis in a single rigorous study\",\n      \"pmids\": [\"18799455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SENP7 C-terminal catalytic domain efficiently depolymerizes poly-SUMO2 chains but has undetectable activity against poly-SUMO1 chains. It shows 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 knockdown leads to accumulation of high-molecular-mass SUMO2 species and accumulation of PML in subnuclear bodies.\",\n      \"method\": \"In vitro isopeptidase assays, siRNA knockdown, subcellular fractionation/localization, immunofluorescence\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (in vitro assay, cellular localization, KD phenotype) replicated key findings from concurrent structural work\",\n      \"pmids\": [\"19392659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A unique sequence insertion (Loop 1) in the SENP6/SENP7 subclass is essential for their proteolytic activity and forms a more extensive interface with SUMO during the proteolytic reaction. Double point mutations on the SUMO surface swap the SUMO2/3 isoform specificity of SENP6 and SENP7 toward SUMO1, identifying the structural basis for SUMO2/3 preference.\",\n      \"method\": \"Structure-based mutagenesis, in vitro biochemical assays, structural comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with biochemical activity assays in a single study demonstrating mechanistic determinants of isoform specificity\",\n      \"pmids\": [\"21878624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SENP7 interacts with KAP1 through HP1α, promotes removal of SUMO2/3 from KAP1, and regulates interaction of chromatin remodeler CHD3 with chromatin. SENP7 is required for chromatin relaxation in response to DNA damage, for homologous recombination repair, and for cellular resistance to DNA-damaging agents.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, chromatin immunoprecipitation, HR repair assays, DNA damage sensitivity assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP establishing binding partners, combined with functional KD phenotypes showing pathway placement in HR repair\",\n      \"pmids\": [\"24018422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SENP7 contains a module of two consecutive HP1 interaction motifs that lock HP1 at pericentric heterochromatin by restricting HP1 mobility. Loss of SENP7 leads to increased time spent in mitosis and reduced HP1 enrichment at pericentric domains. This locking mechanism acts on top of H3K9me3 to maintain HP1 enrichment.\",\n      \"method\": \"Live-cell imaging (FRAP), siRNA knockdown, immunofluorescence, time-lapse microscopy, mutational analysis of HP1-interaction motifs\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP and live imaging directly showing HP1 mobility restriction, combined with mutagenesis of HP1 interaction motifs and mitotic phenotype\",\n      \"pmids\": [\"25660026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SPOP E3 ubiquitin ligase adaptor targets SENP7 for ubiquitin-mediated proteasomal degradation. SPOP-mediated degradation of SENP7 promotes cellular senescence by increasing HP1α SUMOylation, leading to HP1α subcellular re-localization and epigenetic gene silencing. Cancer-associated SPOP mutants fail to degrade SENP7.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, ectopic expression of wild-type and mutant SPOP, immunofluorescence, senescence assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, and functional phenotype (senescence) in single study with multiple orthogonal approaches\",\n      \"pmids\": [\"26527005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"c-Myc is a substrate for SENP7-regulated deSUMOylation. Knockdown of SENP7 increased c-Myc SUMOylation, indicating SENP7 deconjugates SUMO from c-Myc. SUMOylated c-Myc is subsequently ubiquitylated by RNF4 and degraded by the proteasome.\",\n      \"method\": \"siRNA knockdown, mass spectrometry to identify SUMO acceptor lysines, SUMOylation assays\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA KD showing increased c-Myc SUMOylation, with mass spectrometry identifying modification sites, but no direct reconstitution of SENP7 activity on c-Myc\",\n      \"pmids\": [\"25895136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SENP7 interacts with cGAS and catalyzes its deSUMOylation. SUMO is conjugated to cGAS at lysine residues K335, K372, and K382, which suppresses cGAS DNA-binding, oligomerization, and nucleotidyl-transferase activities. SENP7-mediated deSUMOylation of cGAS relieves this inhibition. SENP7 knockdown markedly impaired IRF3-responsive gene expression induced by the cGAS-STING axis.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of cGAS SUMOylation sites, in vitro nucleotidyl-transferase assay, siRNA knockdown, IRF3 reporter assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including Co-IP, site-directed mutagenesis of target lysines, in vitro activity assay, and functional KD phenotype\",\n      \"pmids\": [\"28095500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Maternal SENP7 is required for meiotic progression in mouse oocytes. SENP7-depleted oocytes showed meiotic arrest at prophase I and metaphase I, with histone H3 hyperacetylation and hypomethylation, Cdc14B/C upregulation, CyclinB1/B2 downregulation, defective spindle assembly, and mislocalization/ubiquitylation-mediated proteasomal degradation of γ-tubulin. SENP7-depleted embryos exhibited defective maternal-zygotic transition and failed to produce blastocysts.\",\n      \"method\": \"siRNA microinjection into oocytes, immunofluorescence, Western blotting, live-cell imaging, chromatin staining\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function in oocytes with specific molecular phenotypes including histone modification changes and spindle defects\",\n      \"pmids\": [\"28315713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In steady state, SENP7 expression in intestinal epithelial cells is negatively regulated by direct interaction with and ubiquitination by SIAH2. In IBD, upregulated SENP7 displays a distinct interactome and drives expansion of proinflammatory γδ T cells. In vivo knockdown of SENP7 abrogated DSS-induced gut inflammation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA/shRNA knockdown in vivo, flow cytometry, mouse DSS colitis model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing SIAH2 interaction, ubiquitination assay, and in vivo knockdown with defined inflammatory phenotype\",\n      \"pmids\": [\"31825833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SENP7 catalyzes deSUMOylation of PTEN in response to ROS (oxidative stress) in CD8+ T cells, triggering PTEN degradation and preventing PTEN-dependent metabolic defects. Oxidative stress triggers cytosolic translocation of SENP7, enabling PTEN deSUMOylation. SENP7-deficient CD8+ T cells show decreased glycolysis and oxidative phosphorylation, attenuated proliferation in vitro, and dampened antitumor functions in vivo.\",\n      \"method\": \"SENP7 conditional KO mice, metabolic assays (glycolysis, OXPHOS), Co-immunoprecipitation, subcellular fractionation, in vivo tumor models, human CRC samples\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with metabolic phenotype, Co-IP establishing PTEN interaction, subcellular fractionation showing ROS-triggered translocation, validated in human samples\",\n      \"pmids\": [\"35143421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structure of SENP7 catalytic domain bound to SUMO2 revealed that the Loop1 insertion in SENP7 makes specific contacts with SUMO2 responsible for SUMO2 isoform specificity. Other interface contacts between SENP7 and SUMO2 (including C-terminal tail interaction) are conserved among SENP/ULP family members.\",\n      \"method\": \"X-ray crystallography, structural analysis, comparison with SENP family members\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of SENP7:SUMO2 complex with identification of specific loop contacts, in a single rigorous structural study\",\n      \"pmids\": [\"36334780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SENP7 directly regulates transcription of the myosin heavy chain MyHC-IId gene. SENP7 deSUMOylates flightless-1 (Fli-I), signaling its association with Safb1. SENP7 deficiency leads to higher Fli-I SUMOylation, lower Safb1 chromatin residency, transcriptionally incompetent chromatin on MyHC-IId, sarcomere disorganization, and disrupted muscle cell contraction. Cachexia signaling impedes the SENP7-governed transcriptional program.\",\n      \"method\": \"SENP7 KO muscle cells, ChIP assay, Co-immunoprecipitation, SUMOylation assay, contraction assays, chromatin conformation analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches including Co-IP, SUMOylation assay, ChIP, and functional contraction phenotype establishing pathway from SENP7 to sarcomere organization\",\n      \"pmids\": [\"36417853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SENP7 deSUMOylates perilipin family protein Plin4, promoting Plin4 localization to lipid droplets. Senp7-deficient mice (conventional and adipocyte-specific KO) display reduced white adipose tissue mass, decreased adipocyte size, and significantly smaller lipid droplets.\",\n      \"method\": \"Conditional and conventional KO mice, lipid droplet morphology analysis, SUMOylation assay, Co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent KO mouse models with specific lipid droplet phenotype and direct biochemical demonstration of Plin4 deSUMOylation\",\n      \"pmids\": [\"38677512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SENP7 interacts with IFI204 in microglia, catalyzes the deSUMOylation of IFI204, and promotes STING signal activation, driving microglial pyroptosis and mitochondrial dysfunction.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting, immunofluorescence, molecular docking\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and molecular docking establishing interaction, with functional pyroptosis phenotype, but limited mechanistic depth in the abstract\",\n      \"pmids\": [\"40407969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SENP7 facilitates activation of the cGAS/STING/IRF3 axis by regulating deSUMOylation of cGAS, triggering microglial pyroptosis that leads to neuronal apoptosis. SENP7 knockdown inhibited GSDMD-N, Caspase1, and NLRP3 protein levels and reduced IL-1β and IL-18 concentrations in LPS-ATP-stimulated BV2 cells.\",\n      \"method\": \"Immunoprecipitation SUMOylation assay, siRNA knockdown, Western blotting, co-culture assay\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — SUMOylation assay and KD phenotype corroborating prior cGAS deSUMOylation findings from PMID:28095500 in a neuroinflammatory context\",\n      \"pmids\": [\"39999677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SENP7 promotes regulatory B-cell (Breg) differentiation by activating SIRT1 expression via deSUMOylation, thereby enhancing IL-10 gene expression and inhibiting B-cell senescence.\",\n      \"method\": \"Co-immunoprecipitation, flow cytometry, adoptive transfer experiments, primary mouse cell sorting\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and functional experiments in a single study, limited mechanistic detail on deSUMOylation of SIRT1 in abstract\",\n      \"pmids\": [\"41362746\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SENP7 is a SUMO2/3-specific isopeptidase (confirmed by crystal structure and biochemistry) whose Loop1 insertion confers SUMO2/3 isoform selectivity and poly-SUMO chain disassembly activity; it localizes predominantly to the nucleoplasm where it deSUMOylates substrates including KAP1 (enabling chromatin relaxation for homologous recombination), HP1α (controlling pericentric heterochromatin integrity and mitosis), cGAS (activating innate immune signaling), PTEN (sustaining CD8+ T cell metabolic fitness in response to oxidative stress), Fli-I (coordinating sarcomere assembly via transcriptional regulation of MyHC-IId), Plin4 (promoting lipid droplet maturation in adipocytes), and c-Myc (regulating its proteasomal degradation); SENP7 protein stability is itself controlled by SPOP-mediated ubiquitination and SIAH2-mediated ubiquitination, linking SENP7 to cellular senescence and intestinal inflammation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SENP7 is a SUMO2/3-specific isopeptidase that disassembles poly-SUMO2/3 chains and removes SUMO2/3 from conjugated substrates, acting as a deSUMOylation hub that links chromatin dynamics, innate immune signaling, and cellular metabolism [#0, #1]. Crystallographic and biochemical work established that SENP7 strongly prefers SUMO2/3 over SUMO1, with rates comparable to SENP2 against di- and poly-SUMO2/3, and that a unique Loop1 insertion in the SENP6/SENP7 subclass forms an extensive interface with SUMO2 that confers isoform selectivity and supports poly-SUMO chain deconjugation [#0, #2, #11]. The full-length enzyme localizes predominantly to the nucleoplasm, where its depletion causes accumulation of high-molecular-mass SUMO2/3 conjugates [#1]. In chromatin, SENP7 is recruited through HP1\\u03b1 to deSUMOylate KAP1, controlling CHD3 association and enabling chromatin relaxation required for homologous recombination and resistance to DNA-damaging agents [#3]; a tandem HP1-interaction module additionally locks HP1 at pericentric heterochromatin to maintain its enrichment and proper mitotic progression [#4]. SENP7 deSUMOylates a broad substrate set that defines distinct cellular roles: cGAS, where SUMO removal relieves inhibition of DNA-binding and nucleotidyl-transferase activity to drive cGAS-STING/IRF3 innate immune output [#7]; PTEN, where ROS-triggered cytosolic translocation of SENP7 permits PTEN deSUMOylation, degradation, and sustained CD8+ T cell metabolic fitness and antitumor function [#10]; the transcriptional regulator Fli-I, coordinating Safb1 chromatin residency and MyHC-IId transcription for sarcomere assembly [#12]; and Plin4, promoting its lipid-droplet localization and adipocyte lipid droplet maturation [#13]. SENP7 protein levels are themselves set by ubiquitin ligases: SPOP-mediated degradation restrains SENP7 to promote senescence via HP1\\u03b1 SUMOylation, and SIAH2-mediated ubiquitination keeps SENP7 low in intestinal epithelium, with dysregulated SENP7 driving proinflammatory \\u03b3\\u03b4 T-cell expansion and gut inflammation [#5, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that SENP7 is a SUMO2/3-preferring isopeptidase structurally distinct from SENP1/2, defining its catalytic identity and chain-processing capacity.\",\n      \"evidence\": \"X-ray crystallography of the catalytic domain with in vitro deconjugation assays and structure-guided mutagenesis\",\n      \"pmids\": [\"18799455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No substrate-bound structure to explain isoform selectivity at this stage\", \"Cellular substrates not yet identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Confirmed the SUMO2/3 chain-editing function in cells, showing SENP7 controls high-molecular-mass SUMO2/3 conjugate levels in the nucleoplasm.\",\n      \"evidence\": \"In vitro isopeptidase assays, siRNA knockdown, subcellular fractionation and immunofluorescence\",\n      \"pmids\": [\"19392659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific physiological substrates not defined\", \"Mechanism of nucleoplasmic targeting unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the Loop1 insertion as the structural determinant of SUMO2/3 isoform specificity, explaining why SENP6/SENP7 favor SUMO2/3.\",\n      \"evidence\": \"Structure-based mutagenesis swapping SUMO surface residues with in vitro activity assays\",\n      \"pmids\": [\"21878624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct visualization of the Loop1-SUMO contacts awaited a complex structure\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed SENP7 in the DNA damage response by showing HP1\\u03b1-bridged deSUMOylation of KAP1 enables chromatin relaxation and homologous recombination.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, ChIP, HR repair and DNA damage sensitivity assays\",\n      \"pmids\": [\"24018422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KAP1 deSUMOylation is direct or HP1\\u03b1-dependent for catalysis not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a non-catalytic chromatin role: tandem HP1-interaction motifs lock HP1 at pericentric heterochromatin, coupling SENP7 to mitotic fidelity.\",\n      \"evidence\": \"FRAP live-cell imaging, knockdown, mutational analysis of HP1-interaction motifs, mitotic timing\",\n      \"pmids\": [\"25660026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between the locking function and deSUMOylase activity unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed SENP7 abundance is controlled by SPOP-mediated ubiquitination, linking its turnover to senescence through HP1\\u03b1 SUMOylation.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, wild-type/mutant SPOP expression, senescence assays\",\n      \"pmids\": [\"26527005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of SPOP control across tissues not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended SENP7 substrate range to c-Myc, positioning deSUMOylation upstream of RNF4-mediated proteasomal control of c-Myc.\",\n      \"evidence\": \"siRNA knockdown, mass spectrometry of SUMO acceptor lysines, SUMOylation assays\",\n      \"pmids\": [\"25895136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct in vitro reconstitution of SENP7 acting on c-Myc\", \"Functional consequence for c-Myc target genes not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a positive role for SENP7 in innate immunity by deSUMOylating cGAS to relieve SUMO-mediated suppression of its catalytic and DNA-binding activities.\",\n      \"evidence\": \"Co-IP, site-directed mutagenesis of cGAS SUMO sites, in vitro nucleotidyl-transferase assay, IRF3 reporter\",\n      \"pmids\": [\"28095500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo immune consequence of SENP7 loss not addressed in this study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a maternal requirement for SENP7 in meiotic progression and the maternal-zygotic transition.\",\n      \"evidence\": \"siRNA microinjection in mouse oocytes, immunofluorescence, live imaging, chromatin staining\",\n      \"pmids\": [\"28315713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SUMO substrates driving meiotic phenotypes not identified\", \"Causal link between histone modification changes and spindle defects unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed SIAH2-mediated ubiquitination restrains SENP7 in intestinal epithelium, with dysregulated SENP7 driving proinflammatory \\u03b3\\u03b4 T-cell expansion in IBD.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, in vivo knockdown, flow cytometry, DSS colitis model\",\n      \"pmids\": [\"31825833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SENP7 substrates underlying the inflammatory interactome not defined\", \"Mechanism linking epithelial SENP7 to \\u03b3\\u03b4 T cells incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked SENP7 to T-cell metabolism by showing ROS-triggered cytosolic translocation enables PTEN deSUMOylation and degradation to sustain CD8+ T-cell fitness and antitumor activity.\",\n      \"evidence\": \"Conditional KO mice, metabolic assays, Co-IP, subcellular fractionation, tumor models, human CRC samples\",\n      \"pmids\": [\"35143421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal that triggers SENP7 cytosolic translocation upon ROS not defined\", \"Whether nuclear functions are concurrently affected unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided the SENP7:SUMO2 co-crystal structure, directly visualizing Loop1 contacts that explain SUMO2 isoform specificity.\",\n      \"evidence\": \"X-ray crystallography of the catalytic domain bound to SUMO2 with family comparison\",\n      \"pmids\": [\"36334780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure with a physiological poly-SUMO substrate\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a transcriptional/sarcomere role: SENP7 deSUMOylates Fli-I to promote Safb1 chromatin residency and MyHC-IId transcription for muscle contraction.\",\n      \"evidence\": \"SENP7 KO muscle cells, ChIP, Co-IP, SUMOylation assay, contraction and chromatin conformation analyses\",\n      \"pmids\": [\"36417853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cachexia signaling impedes the SENP7 program mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed SENP7 deSUMOylates Plin4 to drive its lipid-droplet localization, defining a role in adipocyte lipid droplet maturation.\",\n      \"evidence\": \"Conventional and adipocyte-specific KO mice, lipid droplet morphology, SUMOylation assay, Co-IP\",\n      \"pmids\": [\"38677512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SENP7 acts at the lipid droplet itself or upstream in the cytosol not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated SENP7-driven deSUMOylation of cGAS and IFI204 in microglial STING activation and pyroptosis in neuroinflammation.\",\n      \"evidence\": \"Co-IP, SUMOylation assays, siRNA knockdown, molecular docking, co-culture in BV2/microglial models\",\n      \"pmids\": [\"40407969\", \"39999677\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IFI204 interaction relies partly on docking without structural validation\", \"Limited mechanistic depth on deSUMOylation kinetics in these contexts\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended SENP7 function to regulatory B-cell biology via deSUMOylation-dependent activation of SIRT1 and IL-10 expression.\",\n      \"evidence\": \"Co-IP, flow cytometry, adoptive transfer, primary cell sorting\",\n      \"pmids\": [\"41362746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct deSUMOylation of SIRT1 not biochemically reconstituted\", \"SIRT1 SUMO sites not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SENP7 substrate selection and subcellular partitioning are coordinated across its diverse roles (chromatin, immunity, metabolism) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for context-specific substrate recognition\", \"Regulators governing nuclear vs cytosolic localization beyond ROS not defined\", \"No structure of SENP7 engaging a full-length physiological substrate\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 7, 10, 12, 13]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 10, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 9, 15]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KAP1\", \"HP1\\u03b1\", \"CHD3\", \"cGAS\", \"PTEN\", \"Fli-I\", \"Plin4\", \"SPOP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}