{"gene":"SENP1","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2003,"finding":"SENP1 is a nuclear-localized SUMO-specific cysteine protease; mutation of the N-terminal nuclear localization signal causes cytoplasmic accumulation; mutation of the active-site cysteine (dominant-negative) causes accumulation of high-molecular-weight SUMO-1 conjugates; the N-terminal regulatory domain suppresses constitutive catalytic activity of the core domain; SENP1 itself is a target for SUMO-1 modification at a nonconsensus site; SENP1 localization is influenced by SUMO-1-conjugated target proteins.","method":"Mutagenesis of NLS and catalytic cysteine, subcellular localization by imaging, immunoprecipitation, dominant-negative overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — active-site mutagenesis, NLS mutagenesis, localization experiments, and dominant-negative phenotype in a single focused study","pmids":["14563852"],"is_preprint":false},{"year":2004,"finding":"SENP1 enhances androgen receptor (AR)-dependent transcription not by deSUMOylating AR itself, but by deconjugating SUMO from HDAC1, thereby reducing HDAC1 deacetylase activity; RNAi depletion of HDAC1 reduced SENP1's transcriptional enhancement effect.","method":"Transcriptional reporter assays, RNAi knockdown of HDAC1, co-immunoprecipitation, in vitro deSUMOylation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro deSUMOylation, RNAi epistasis, reporter assay, multiple orthogonal methods in one study","pmids":["15199155"],"is_preprint":false},{"year":2005,"finding":"SENP1 processes all SUMO-1, -2, and -3 precursors in vitro, with highest efficiency for SUMO-1 followed by SUMO-2 and SUMO-3; the catalytic domain alone determines substrate specificity; two residues immediately after the 'GG' region of SUMO precursors determine differential maturation efficiency.","method":"In vitro protease assay with purified recombinant SENP1, mutagenesis of SUMO precursor C-terminal fragments","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro cleavage assay with mutagenesis, single lab but multiple substrates tested","pmids":["15487983"],"is_preprint":false},{"year":2005,"finding":"Retroviral insertional mutation of mouse SENP1/SuPr-2 increases steady-state levels of sumoylated proteins and causes placental abnormalities and embryonic lethality, demonstrating that deSUMOylation by SENP1 is essential for mammalian development.","method":"Retroviral insertional mutagenesis in mice, Western blot for SUMO conjugates, embryonic phenotyping","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in vivo with defined molecular phenotype (global hyperSUMOylation) and specific developmental readout","pmids":["15923632"],"is_preprint":false},{"year":2005,"finding":"SENP1 deSUMOylates HIPK2 both in vitro and in cells; SENP1 contains a nuclear export sequence (NES) in its C-terminal region and shuttles between cytoplasm and nucleus; forced nuclear localization of SENP1 or NES mutation enhances HIPK2 deSUMOylation and induces dissociation of HIPK2 from nuclear bodies.","method":"In vitro deSUMOylation assay, NES mutagenesis, co-immunoprecipitation, subcellular localization imaging","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro assay plus cellular mutagenesis and localization, single lab","pmids":["16253240"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of SENP1 catalytic domain C603S mutant in complex with SUMO-1 at 2.8 Å resolution reveals that SENP1 requires a self-conformational change prior to peptide/isopeptide bond cleavage; four unique SENP1 residues facilitate SUMO-1 binding; SENP1 can also hydrolyze the thioester linkage in E1-SUMO and E2-SUMO intermediates.","method":"X-ray crystallography, in vitro protease activity assay with active-site mutant, structural comparison with SENP2","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro functional validation, reveals novel hydrolytic activity on E1/E2-SUMO thioesters","pmids":["16712526"],"is_preprint":false},{"year":2008,"finding":"In resting endothelial cells, SENP1 resides in the cytoplasm complexed with thioredoxin; TNF stimulation releases SENP1 from thioredoxin in a ROS-dependent manner and induces SENP1 nuclear translocation; nuclear SENP1 deSUMOylates HIPK1, promoting its cytoplasmic translocation and ASK1-JNK activation leading to apoptosis; catalytic-inactive SENP1 mutant and siRNA of SENP1 block this pathway.","method":"Co-immunoprecipitation, siRNA knockdown, catalytic mutant overexpression, SENP1-KO MEFs, subcellular fractionation/localization","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, catalytic mutant, siRNA, and KO MEF validation across multiple orthogonal methods","pmids":["18219322"],"is_preprint":false},{"year":2008,"finding":"Among SENPs tested (1, 2, 3, 5, 6), only SENP1 and SENP2 efficiently cleave AR-SUMO-1 conjugates in intact cells and in vitro; androgens induce rapid SUMO-1 conjugation of AR; SENP1 reverses ligand-induced AR SUMOylation and promotes AR-dependent transcription in a catalytic activity-dependent and promoter-selective manner; SENP1 knockdown attenuates AR target gene expression and androgen-stimulated LNCaP cell growth.","method":"In vitro deSUMOylation assay, in-cell SUMOylation assay, siRNA knockdown, transcriptional reporter assay","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro assay, cellular knockdown, reporter assays, multiple SENPs compared, single lab","pmids":["19116244"],"is_preprint":false},{"year":2008,"finding":"IL-6 induces SENP1 mRNA expression; SENP1 deSUMOylates PML, disrupting PML bodies and relieving PML-mediated suppression of STAT3 activation; catalytically inactive SENP1 fails to reverse PML suppression of STAT3.","method":"Co-immunoprecipitation, catalytic mutant, Western blot, STAT3 reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — single lab, catalytic mutant and Co-IP but limited mechanistic depth","pmids":["18474224"],"is_preprint":false},{"year":2010,"finding":"SENP1 deSUMOylates GATA1 directly (demonstrated in vitro); SENP1 knockout mice develop anemia with fetal liver erythropoiesis defects; SUMOylated GATA1 accumulates in SENP1-KO livers and shows reduced DNA binding at GATA1-responsive gene promoters; GATA1-dependent gene expression and erythropoiesis are restored by SENP1-mediated deSUMOylation.","method":"SENP1 conditional knockout mice, in vitro deSUMOylation assay, bone marrow transplant, ChIP, Western blot","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic KO with defined erythropoiesis phenotype, in vitro reconstitution, ChIP, multiple orthogonal methods","pmids":["20457756"],"is_preprint":false},{"year":2010,"finding":"HIF-1α is a direct transcriptional activator of SENP1 (via hypoxia response element on Senp1 promoter); SENP1 in turn deSUMOylates and stabilizes HIF-1α, forming a positive feedback loop; SENP1 silencing decreases VEGF production and endothelial cell angiogenic function; SENP1-null embryos show reduced vascular endothelial cells.","method":"ChIP, HRE promoter mutation, siRNA knockdown, angiogenesis assays, SENP1-KO embryo analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, promoter mutagenesis, siRNA, KO embryo analysis across multiple orthogonal methods","pmids":["20841360"],"is_preprint":false},{"year":2010,"finding":"SENP1 overexpression in rheumatoid arthritis synovial fibroblasts decreases histone H4 acetylation at the MMP-1 promoter, reduces MMP-1 expression and invasiveness; this effect is dependent on HDAC4 accumulation at the MMP-1 promoter; SENP1 fails to modulate MMP-1 in HDAC4-silenced cells.","method":"SENP1 overexpression, siRNA knockdown of HDAC4, ChIP, RT-PCR, invasion assay","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ChIP, epistasis by HDAC4 siRNA, single lab with multiple methods","pmids":["20079608"],"is_preprint":false},{"year":2010,"finding":"SENP1 overexpression in prostate cancer promotes HIF-1α stabilization, VEGF production, and angiogenesis; androgen-driven SENP1 transgene in mice induces high-grade prostatic intraepithelial neoplasia; SENP1 also enhances AR- and cyclin D1-dependent prostate epithelial cell proliferation.","method":"Transgenic mouse model, immunohistochemistry, cell proliferation assays, VEGF measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with defined molecular pathway, single lab","pmids":["20551310"],"is_preprint":false},{"year":2012,"finding":"SENP1 and SENP2 are targeted to kinetochores in mitosis; SENP1 knockdown delays sister chromatid separation at metaphase; proper spatial and temporal control of sumoylation at kinetochores by SENP1 is required for chromosome segregation.","method":"siRNA knockdown, live-cell imaging, kinetochore targeting assays, chromosome segregation analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with specific mitotic phenotype, localization data, single lab","pmids":["24048451"],"is_preprint":false},{"year":2012,"finding":"Nup153 interacts with SENP1 through its N-terminal domain; SENP1 and SENP2 co-depletion increases sumoylation of endogenous Nup153; SENP1 levels are influenced by Nup153 abundance (whereas SENP2 is not), suggesting Nup153 anchors SENP1 at the nuclear pore complex.","method":"Co-immunoprecipitation, RNAi depletion, dominant-negative mutants, Western blot for SUMO conjugates","journal":"Nucleus","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP and RNAi with substrate accumulation, single lab","pmids":["22688647"],"is_preprint":false},{"year":2012,"finding":"SENP1 and SENP2 co-depletion causes mislocalization and reduced levels of multiple nucleoporins, revealing a role for pore-associated SENPs in nucleoporin homeostasis and nuclear pore complex configuration; transport is altered under these conditions.","method":"siRNA co-depletion, immunofluorescence, transport kinetics assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with localization and functional transport readout, single lab","pmids":["24196834"],"is_preprint":false},{"year":2012,"finding":"SENP1 deficiency increases ER stress-induced apoptosis by accumulating SUMOylated XBP1; SENP1 directly deSUMOylates XBP1 and increases its transcriptional activity; XBP1 target genes are downregulated in SENP1-KO cells under ER stress.","method":"SENP1-KO cells, in vitro deSUMOylation assay, transcriptional reporter assay, Western blot","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells, in vitro assay, reporter assay, single lab","pmids":["22370484"],"is_preprint":false},{"year":2013,"finding":"SENP1 binds to and deSUMOylates Pin1 on Lys6 (WW domain) and Lys63 (PPIase domain); Pin1 SUMOylation inhibits its isomerase activity and oncogenic function; SENP1-mediated deSUMOylation promotes Pin1 oncogenic activity (centrosome amplification, cell transformation) and increases Pin1 protein stability.","method":"Co-immunoprecipitation, in vitro deSUMOylation assay, site-directed mutagenesis, cell transformation assay, centrosome amplification assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro assay, mutagenesis of SUMOylation sites, Co-IP, multiple functional readouts, single lab","pmids":["23633483"],"is_preprint":false},{"year":2014,"finding":"SENP1 regulates mitochondrial gene expression via deSUMOylation of MEF-2C, which enhances MEF-2C-mediated PGC-1α transcription; SENP1 expression in cardiomyocytes is induced by hypertrophic stimuli through calcium/calcineurin-NFAT3; genetic induction of SENP1 leads to mitochondrial dysregulation and cardiac dysfunction.","method":"Cardiomyocyte SENP1 transgenic mouse, co-immunoprecipitation, Western blot, gene expression analysis","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model, Co-IP, pathway analysis, single lab","pmids":["25446185"],"is_preprint":false},{"year":2014,"finding":"NMR relaxation measurements reveal that the β-grasp domain of SUMO-1 binding to SENP1's exosite induces structural changes ~20 Å away at the active site (including dynamics of 'lid' residue Trp465), allosterically activating the enzyme; this remote substrate-induced activation is required for efficient catalysis.","method":"NMR relaxation measurements, chemical shift perturbation, enzyme kinetic analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural study combined with enzyme kinetics in a single rigorous study","pmids":["25263960"],"is_preprint":false},{"year":2015,"finding":"SENP1 is required for amplification of glucose-stimulated insulin exocytosis in pancreatic β-cells; the ICDc pathway generates NADPH, leading to glutathione (GSH) reduction, which activates SENP1 to amplify exocytosis at the distal exocytotic site; islet-specific Senp1 deletion in mice causes impaired glucose tolerance by reducing this amplification; the pathway is impaired in human T2D and can be rescued by SENP1 pathway intermediates.","method":"Islet-specific Senp1 KO mice, patch-clamp exocytosis measurements, glucose tolerance test, introduction of signaling intermediates into human T2D islets","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — islet-specific KO mice, human islet rescue experiments, patch-clamp, multiple orthogonal methods across labs","pmids":["26389676"],"is_preprint":false},{"year":2015,"finding":"Adipocyte-specific deletion of SENP1 enhances SUMOylation of NEMO (NF-κB essential molecule) at lysine 277/309, leading to increased NF-κB activity, proinflammatory cytokine production, pancreatic inflammation and type-1 diabetes-like phenotype; NF-κB inhibitors reverse β-cell damage and T1DM phenotype in SENP1-deficient mice.","method":"Adipocyte-specific SENP1-KO mice, Co-IP, site-directed mutagenesis of NEMO K277/309, NF-κB reporter, cytokine measurement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO, site-specific mutagenesis, pharmacological rescue, multiple orthogonal methods","pmids":["26596471"],"is_preprint":false},{"year":2016,"finding":"Molecular dynamics simulations combined with the crystal structure show that SUMO1 β-grasp domain binding to the SENP1 exosite cleft allosterically activates SENP1 via a dock-and-coalesce mechanism: the β-grasp wedges open the exosite cleft, enabling docking of the SUMO C-terminus proximal portion, and strengthened cross-channel correlated motions allow the distal portion to coalesce at the catalytic center.","method":"Molecular dynamics simulation based on crystal structure, analysis of conformational and dynamic changes","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 1 (structural/computational) / Weak — computational study based on existing crystal structure, no independent wet-lab validation in this paper","pmids":["27576863"],"is_preprint":false},{"year":2016,"finding":"Senp1 drives hypoxia-induced erythrocytosis via GATA1 and Bcl-xL; altering SENP1 levels in CMS iPSC-derived erythroid cells converts the CMS erythropoietic phenotype to non-CMS and vice versa; GATA1 is an essential downstream target of SENP1 in this context.","method":"iPSC technology, lentiviral SENP1 manipulation, erythroid differentiation assays, Western blot","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — iPSC functional rescue/loss experiments, replicated GATA1 finding, single lab","pmids":["27821551"],"is_preprint":false},{"year":2017,"finding":"SENP1 directly deSUMOylates HIF-1α, increasing its stability and transcriptional activity; HIF-1/2α directly transcribes SENP1 through hypoxia response elements; a positive feedback loop between SENP1 and HIF-1α drives hepatocellular carcinoma stemness under hypoxia.","method":"Immunoprecipitation for SUMO-HIF-1α, ChIP for HIF binding to SENP1 HRE, quantitative PCR, in vivo xenograft","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, in vivo model, multiple orthogonal methods","pmids":["28258134"],"is_preprint":false},{"year":2017,"finding":"SENP1 deSUMOylates PTP1B; in SENP1-deficient macrophages, highly SUMOylated PTP1B fails to de-phosphorylate STAT3, leading to STAT3 activation which induces SOCS3 and suppresses STAT1 signaling; this SENP1→PTP1B→STAT3→SOCS3 axis negatively regulates IFN-γ-STAT1-mediated M1 macrophage activation.","method":"SENP1-KO macrophages, Co-IP/SUMOylation assays, phospho-STAT Western blot, Listeria infection assay","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO macrophages with defined pathway readout, Co-IP, single lab","pmids":["27702761"],"is_preprint":false},{"year":2017,"finding":"SENP1-modulated sumoylation regulates RB and Lamin A/C interaction; SUMO1 conjugation of both RB and Lamin A/C is required for their interaction; SENP1 removes SUMO1 from both proteins; this SUMO1-dependent RB-Lamin A/C complex protects both proteins from proteasomal degradation.","method":"Co-immunoprecipitation, SUMO site mutagenesis, proteasome inhibitor experiments, Western blot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, mutagenesis, proteasome assay, single lab","pmids":["27270425"],"is_preprint":false},{"year":2017,"finding":"SENP1 deSUMOylates PTEN; in the absence of SENP1, SUMO1-modified PTEN is sequestered in the cytosol where it binds to SUMOylated WWP2 (E3 ubiquitin ligase), promoting PTEN ubiquitylation and degradation; SENP1 thereby blocks SUMO1-dependent ubiquitylation of PTEN.","method":"Co-immunoprecipitation, SUMOylation assays, SENP1 transgenic and KO cells, subcellular fractionation","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, subcellular fractionation, SENP1 transgenic/KO models, single lab","pmids":["27852060"],"is_preprint":false},{"year":2017,"finding":"Hypoxia triggers SENP1-mediated deSUMOylation of KLF15 in pulmonary endothelial cells, causing KLF15 translocation from nucleus to cytoplasm; nuclear KLF15 normally represses Arg2 transcription; SENP1-mediated KLF15 deSUMOylation therefore de-represses Arg2 (arginase 2), contributing to endothelial dysfunction.","method":"Co-immunoprecipitation, subcellular fractionation, ChIP, SENP1 overexpression/knockdown, isolated pulmonary artery ring assay","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, functional vascular assay, single lab","pmids":["29472234"],"is_preprint":false},{"year":2017,"finding":"Senp1 knockdown in nuclear pore complex (Nup153-depleted cells) displaces SENP1 from NPCs; artificial tethering of SENP1 to NPCs restores non-homologous end joining and 53BP1 sumoylation; proper NPC localization of SENP1 is required for 53BP1 SUMO1 modification and efficient NHEJ DNA repair.","method":"siRNA depletion, artificial tethering of SENP1 to NPC, NHEJ reporter assay, immunofluorescence, SUMO Western blot","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — NPC tethering rescue experiment, NHEJ reporter, single lab with multiple methods","pmids":["28576968"],"is_preprint":false},{"year":2018,"finding":"SENP1 interacts with and deSUMOylates c-Myc in cells and in vitro; overexpression of wild-type but not catalytically inactive C603S SENP1 stabilizes c-Myc; SENP1-mediated deSUMOylation reduces c-Myc polyubiquitination, inhibiting proteasomal degradation; deSUMOylation promotes monoubiquitinated c-Myc and phosphorylation at S62 and T58.","method":"Co-immunoprecipitation, in vitro deSUMOylation assay, catalytic mutant (C603S), siRNA knockdown, ubiquitination assay, Western blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution, catalytic mutant, Co-IP, ubiquitination assay, multiple orthogonal methods in one study","pmids":["30305424"],"is_preprint":false},{"year":2018,"finding":"Streptonigrin binds SENP1 at the SUMO-binding surface, disrupting SENP1-SUMO1 interaction; NMR identified binding site with key aromatic π-stacking interactions; streptonigrin treatment increases global SUMOylation and reduces HIF-1α levels in cells.","method":"NMR chemical shift perturbation, site-directed mutagenesis, global SUMOylation assay, HIF-1α Western blot","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR binding study with mutagenesis, single lab","pmids":["29481054"],"is_preprint":false},{"year":2019,"finding":"SENP1 deSUMOylates Sirt3 in mitochondria; SUMOylation suppresses Sirt3 deacetylase activity; during fasting, SENP1 translocates into mitochondria and activates Sirt3 by deSUMOylation, leading to decreased acetylation of mitochondrial proteins and increased fatty acid oxidation; Sirt3 SUMOylation-deficient mutation reduces fat mass and antagonizes HFD-induced obesity.","method":"Co-immunoprecipitation, in vitro deSUMOylation assay, SENP1-KO mice, Sirt3 SUMOylation mutant knock-in mice, subcellular fractionation, metabolic phenotyping","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro assay, KO mice, knock-in mutant mice, mitochondrial fractionation, multiple independent experiments","pmids":["31302001"],"is_preprint":false},{"year":2019,"finding":"SENP1 deSUMOylates USP28; SUMOylation of USP28 in normoxia suppresses its deubiquitinase activity towards HIF-1α; hypoxia activates SENP1-mediated USP28 deSUMOylation, enhancing USP28 activity to accumulate HIF-1α, forming a SENP1-USP28-HIF-1α positive feedback loop.","method":"Co-immunoprecipitation, GST pull-down, in vivo deSUMOylation assay, luciferase reporter, in vitro deubiquitinase assay","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays (Co-IP, GST pulldown, in vitro assay), single lab","pmids":["30622440"],"is_preprint":false},{"year":2019,"finding":"SENP1 deSUMOylates JAK2; deSUMOylation of JAK2 leads to its cytoplasmic accumulation and activation; the RUNX2-driven SENP1/JAK2 axis mediates platinum resistance in ovarian cancer; SENP1 inhibition or deficiency overcomes platinum resistance.","method":"Co-immunoprecipitation, SUMOylation assay, subcellular fractionation, siRNA/shRNA knockdown, platinum resistance assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, fractionation, functional drug resistance assay, single lab","pmids":["33795649"],"is_preprint":false},{"year":2020,"finding":"SENP1 deSUMOylates IDOL (E3 ubiquitin ligase) at K293; IDOL SUMOylation counteracts its autoubiquitination and elevates IDOL protein levels; SENP1 overexpression increases LDLR protein levels and LDL uptake by removing IDOL SUMOylation; loss of SENP1 lowers LDLR in an IDOL-dependent manner.","method":"Co-immunoprecipitation, SUMOylation assay, SENP1 overexpression/knockdown, LDL uptake assay, Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, functional LDL uptake assay, epistasis by IDOL, single lab","pmids":["33154164"],"is_preprint":false},{"year":2020,"finding":"SENP1 deSUMOylates and stabilizes UBE2T; SENP1 knockout impairs HCC growth, migration and invasion; UBE2T overexpression or K8R (SUMOylation-deficient) mutation promotes cell growth and migration; the SENP1-UBE2T-Akt pathway mediates SENP1's carcinogenic activity.","method":"SENP1 KO cell model, Co-immunoprecipitation, deSUMOylation assay, UBE2T K8R mutagenesis, Akt signaling Western blot, in vivo xenograft","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KO cells, Co-IP, mutagenesis, in vivo model, single lab","pmids":["31969492"],"is_preprint":false},{"year":2021,"finding":"Glucose limitation activates AMPK, which promotes SENP1-mediated Sirt3 deSUMOylation in T cell mitochondria; activated Sirt3 deacetylates mitochondrial metalloprotease YME1L1, suppressing its cleavage of OPA1 and facilitating mitochondrial fusion; this promotes T cell survival and memory development; fructose-1,6-bisphosphate (FBP) negatively regulates AMPK and suppresses the SENP1-Sirt3 axis.","method":"T cell-specific SENP1 and Sirt3 KO mice, co-immunoprecipitation, acetylation assays, mitochondrial morphology imaging, T cell memory assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple KO mouse models, Co-IP, acetylation assay, mitochondrial imaging, functional memory readout across orthogonal methods","pmids":["34272364"],"is_preprint":false},{"year":2021,"finding":"SENP1 deSUMOylates RIPK1 within the TNF-R1 signaling complex (TNF-RSC); loss of SENP1 causes RIPK1 SUMOylation, re-orchestrates TNF-RSC, modulates RIPK1 ubiquitination patterns and activates RIPK1 kinase-dependent apoptosis; hepatocyte-specific SENP1-KO mice develop spontaneous NASH-related phenotypes reversed by RIPK1 kinase inhibition.","method":"Hepatocyte-specific SENP1-KO mice, Co-immunoprecipitation of TNF-RSC, RIPK1 SUMOylation/ubiquitination assays, genetic RIPK1 kinase inhibition rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO, TNF-RSC Co-IP, RIPK1 modification assays, genetic rescue, multiple orthogonal methods","pmids":["36414671"],"is_preprint":false},{"year":2021,"finding":"SENP1 promotes SENP1-Sirt3-GLUD1 axis in macrophages: SENP1 deSUMOylates Sirt3 to activate it; activated Sirt3 deacetylates GLUD1 (glutamate dehydrogenase 1), increasing its activity; increased GLUD1 activity promotes glutaminolysis and α-ketoglutarate accumulation, driving Jmjd3-dependent H3K27me3 demethylation and M2 macrophage polarization.","method":"SENP1-KO macrophages, co-immunoprecipitation, GLUD1 deacetylation assay, metabolomics, H3K27me3 ChIP","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO macrophages, Co-IP, enzymatic assay, metabolomics, ChIP, multiple orthogonal methods","pmids":["35417703"],"is_preprint":false},{"year":2021,"finding":"De novo heterozygous truncating mutation of SENP1 causes autistic-like symptoms in humans and mice; Senp1+/- mice show social deficits and repetitive behaviors with impaired inhibitory/excitatory synaptic function in the retrosplenial agranular (RSA) cortex; loss of SENP1 increases SUMOylation and degradation of FMRP; re-introduction of SENP1 or FMRP in the RSA fully rescues synaptic and behavioral deficits.","method":"Human genetic mutation identification, Senp1+/- mice behavioral and electrophysiology assays, FMRP SUMOylation/degradation assay, stereotaxic virus rescue in RSA","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — human mutation, KO mouse phenotype, FMRP SUMOylation assay, region-specific in vivo rescue, multiple orthogonal methods","pmids":["34731627"],"is_preprint":false},{"year":2021,"finding":"SENP1 deSUMOylates NEMO in microglia; overexpression of SENP1 inhibits IH-induced NEMO SUMOylation and NF-κB activation; SENP1-mediated NEMO deSUMOylation reduces neuroinflammation; siRNA-NEMO abolishes SENP1's protective effect, confirming NEMO as the relevant substrate.","method":"Co-immunoprecipitation, SUMOylation Western blot, siRNA epistasis for NEMO, NF-κB reporter assay","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, siRNA epistasis, single lab","pmids":["34120412"],"is_preprint":false},{"year":2022,"finding":"SENP1 deSUMOylates KLF4; the SENP1-KLF4 axis promotes M1 macrophage polarization through NF-κB signaling; KLF4 SUMOylation deficiency (mirroring SENP1 activity) weakens tumor cell activity in co-culture.","method":"Co-immunoprecipitation, KLF4 SUMOylation assay, NF-κB reporter, macrophage polarization assay","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, functional polarization assay, single lab","pmids":["35942612"],"is_preprint":false},{"year":2023,"finding":"SENP1 deSUMOylates RNF168; SUMOylated RNF168 undergoes liquid-liquid phase separation (LLPS), restricting its recruitment to DNA damage sites, reducing H2A ubiquitination, retaining 53BP1 in nuclear condensates, and impairing NHEJ; SENP1 prevents RNF168 LLPS by removing SUMO, promoting DNA repair and chemotherapy resistance.","method":"Co-immunoprecipitation, SUMOylation assay, in vitro LLPS assay, H2A ubiquitination assay, NHEJ reporter, siRNA/shRNA knockdown","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical and cell biology assays, in vitro LLPS, functional NHEJ readout, single lab","pmids":["37350666"],"is_preprint":false},{"year":2023,"finding":"SENP1 deSUMOylates MAVS, inhibiting its PIAS3-induced poly-SUMOylation; poly-SUMOylation promotes K63-linked polyubiquitination and MAVS aggregation; SUMO conjugation enables MAVS phase separation through a newly identified SUMO-interacting motif (SIM) in MAVS; IRF3 is recruited to MAVS phase-separated droplets via a SIM in IRF3; IRF3 phosphorylation disables SIM-SUMO interactions, releasing activated IRF3.","method":"Co-immunoprecipitation, in vitro LLPS assay, ubiquitination assay, IRF3 phosphorylation assay, mutagenesis of MAVS/IRF3 SIM motifs","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reconstituted LLPS, Co-IP, mutagenesis, ubiquitination assays in one rigorous study","pmids":["37188808"],"is_preprint":false},{"year":2023,"finding":"SENP1 deSUMOylates RIPK1 to inhibit apoptosis; SENP1 deSUMOylates Sirt3 in mitochondria during ischemia; AMPK activation by metformin promotes SENP1-Sirt3 axis, decreasing mitochondrial SOD2 acetylation, reducing mtROS, and protecting against acute kidney injury.","method":"AKI mouse models, Sirt3 SUMOylation site mutant knock-in (Sirt3 KR) mice, AMPK activation by metformin, metabolomics, Western blot for acetylated SOD2, Co-IP","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mutant mice, pharmacological AMPK activation, metabolomics, single lab","pmids":["37608549"],"is_preprint":false},{"year":2023,"finding":"H2S S-sulfhydrates SENP1 at C683, suppressing its protease activity; in diabetic cardiomyopathy, exogenous H2S S-sulfhydrates SENP1, increasing SERCA2a SUMOylation, improving SERCA2a expression and activity, calcium homeostasis and cardiomyocyte survival; SENP1 C683A mutant (non-sulfhydratable) abolishes these effects.","method":"SENP1 C683A mutagenesis, co-immunoprecipitation, SUMOylation assay, SERCA2a activity assay, calcium imaging, cardiac function measurement","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific mutagenesis, functional SERCA2a assay, Co-IP, single lab","pmids":["36750014"],"is_preprint":false},{"year":2024,"finding":"SENP1 redox sensing in β-cells requires a thiol group at C535 which, together with Zn2+-binding, suppresses basal protease activity and unrestrained exocytosis; a more reduced cytosolic redox state after high-fat diet increases β-cell exocytosis in a SENP1-dependent manner; pancreas- and β-cell-specific SENP1 KO mice fail to upregulate exocytosis and become rapidly glucose intolerant after 2-day HFD.","method":"C535 mutagenesis, β-cell-specific and pancreas-specific SENP1 KO mice, patch-clamp exocytosis, redox measurements, glucose tolerance test","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — active-site mutagenesis, multiple tissue-specific KO models, patch-clamp, redox assay across multiple orthogonal methods","pmids":["38184650"],"is_preprint":false},{"year":2024,"finding":"SENP1 deSUMOylates HDAC2; SENP1-mediated HDAC2 deSUMOylation enhances EGFR transcription and activates the AKT pathway in AML; IGF2BP3 binds the SENP1 3'-UTR in an m6A-dependent manner to upregulate SENP1 expression.","method":"Co-immunoprecipitation, SUMO assay, ChIP-qPCR, MERIP-qPCR, dual-luciferase reporter","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, ChIP, reporter assay, single lab","pmids":["38822351"],"is_preprint":false},{"year":2024,"finding":"SENP1 deSUMOylates HSP90ab1 in cardiomyocytes; loss of SENP1 increases HSP90ab1 SUMOylation, leading to STAT3 activation and fibronectin secretion, which promotes fibroblast activation and cardiac fibrosis; mutation of HSP90ab1 Lys72 (SUMOylation site) or SENP1 overexpression ameliorates adverse ventricular remodeling after myocardial infarction.","method":"Cardiomyocyte-specific SENP1 KO and overexpression mice, Co-immunoprecipitation, HSP90ab1 K72 mutagenesis, cardiac function and fibrosis assessment","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO and OE mice, site mutagenesis, Co-IP, single lab","pmids":["38992961"],"is_preprint":false},{"year":2024,"finding":"SENP1 deSUMOylates ACSL4, reducing its protein stability via removal of SUMO1; SENP1 inhibition in HNSCC increases ACSL4 SUMOylation and stabilization, promoting ferroptosis; SENP1 also regulates GPX4 expression to control ferroptosis.","method":"Co-immunoprecipitation, Western blot for ACSL4 stability, ferroptosis assays (iron, MDA, GSH), shRNA knockdown","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, functional ferroptosis assay, single lab","pmids":["38186303"],"is_preprint":false}],"current_model":"SENP1 is a nuclear/mitochondrial-localizing SUMO-specific cysteine protease (with redox-regulated activity at C535 and allosteric activation by the SUMO β-grasp domain) that deSUMOylates a broad range of substrates—including HIF-1α, GATA1, HDAC1, AR, c-Myc, Pin1, RIPK1, MAVS, RNF168, Sirt3, JAK2, NEMO, FMRP, KLF4, KLF15, IDOL, PTEN, UBE2T, p53, XBP1, HSP90ab1, ACSL4, PTP1B, and others—to regulate transcription, mitochondrial metabolism, DNA damage repair, innate immune signaling, erythropoiesis, insulin secretion, and cell death, with its mitochondrial translocation during metabolic stress (fasting, hypoxia) controlled via AMPK and with subcellular localization anchored at the nuclear pore complex through Nup153."},"narrative":{"mechanistic_narrative":"SENP1 is a SUMO-specific cysteine protease that both matures SUMO precursors and reverses SUMO conjugation on hundreds of substrates, thereby acting as a master regulator of transcription, metabolism, DNA repair, immune signaling, and cell death [PMID:14563852, PMID:15487983]. Catalytically, it processes SUMO-1, -2, and -3 precursors with its isolated catalytic domain dictating specificity, and it additionally hydrolyzes the thioester linkages of E1-SUMO and E2-SUMO intermediates; cleavage requires a substrate-induced conformational change in which binding of the SUMO β-grasp domain to a distal exosite allosterically activates the active site ~20 Å away [PMID:15487983, PMID:16712526, PMID:25263960]. Its protease output is gated by redox and metal chemistry—a reactive thiol at C535 together with Zn2+ suppresses basal activity, and S-sulfhydration at C683 inhibits the enzyme—linking SENP1 activity to cellular redox state [PMID:36750014, PMID:38184650]. SENP1 is predominantly nuclear via an N-terminal NLS, shuttles through a C-terminal NES, and is anchored at the nuclear pore complex by Nup153, a localization required for 53BP1 SUMOylation and non-homologous end joining [PMID:14563852, PMID:16253240, PMID:22688647, PMID:28576968]; loss-of-function in mice causes global hyperSUMOylation, placental defects, and embryonic lethality, establishing deSUMOylation as essential for development [PMID:15923632]. Functionally, SENP1 deSUMOylates and stabilizes HIF-1α in a hypoxia-driven positive feedback loop driving angiogenesis and tumor stemness [PMID:20841360, PMID:28258134], activates erythroid GATA1 to control erythropoiesis [PMID:20457756, PMID:27821551], and translocates into mitochondria upon AMPK activation during metabolic stress to deSUMOylate and activate Sirt3, reprogramming mitochondrial acetylation, fatty-acid oxidation, and immune-cell metabolism [PMID:31302001, PMID:34272364, PMID:35417703]. It governs cell-death and inflammatory signaling by deSUMOylating RIPK1 within the TNF receptor complex, NEMO to restrain NF-κB, and MAVS to limit antiviral phase separation [PMID:36414671, PMID:34120412, PMID:37188808], and it counteracts SUMO-driven liquid-liquid phase separation of RNF168 to promote DNA repair [PMID:37350666]. A de novo heterozygous truncating SENP1 mutation causes autistic-like behavior by destabilizing FMRP, a phenotype rescued by restoring SENP1 in the retrosplenial cortex [PMID:34731627].","teleology":[{"year":2003,"claim":"Established SENP1 as a nuclear SUMO-specific protease whose catalytic cysteine is required to reverse SUMO-1 conjugation and whose activity and localization are internally autoregulated.","evidence":"NLS and active-site cysteine mutagenesis with dominant-negative overexpression and localization imaging","pmids":["14563852"],"confidence":"High","gaps":["Did not define physiological substrates","Regulatory-domain suppression mechanism not structurally resolved"]},{"year":2005,"claim":"Defined the catalytic scope of SENP1, showing it both matures SUMO-1/-2/-3 precursors and that the catalytic domain alone confers substrate specificity.","evidence":"In vitro protease assays with recombinant SENP1 and SUMO precursor mutagenesis","pmids":["15487983"],"confidence":"High","gaps":["In vitro efficiencies may not reflect cellular substrate preference","Did not address isopeptidase vs endopeptidase balance in cells"]},{"year":2005,"claim":"Demonstrated that SENP1 deSUMOylation is essential for mammalian development, linking enzyme loss to global hyperSUMOylation in vivo.","evidence":"Retroviral insertional mutagenesis in mice with SUMO-conjugate Western blots and embryonic phenotyping","pmids":["15923632"],"confidence":"High","gaps":["Did not pinpoint which substrate(s) drive lethality","Insertional allele may be hypomorphic rather than null"]},{"year":2006,"claim":"Provided the structural basis for catalysis, revealing a required self-conformational change and an unexpected ability to cleave E1/E2-SUMO thioesters.","evidence":"X-ray crystallography of the SENP1-SUMO1 catalytic complex with in vitro activity assays","pmids":["16712526"],"confidence":"High","gaps":["Static structure did not capture the activation dynamics","Physiological role of thioester hydrolysis not established"]},{"year":2014,"claim":"Resolved how substrate binding activates SENP1, showing the SUMO β-grasp domain triggers allosteric activation at a remote active site.","evidence":"NMR relaxation and chemical-shift perturbation with enzyme kinetics, later supported by molecular dynamics","pmids":["25263960","27576863"],"confidence":"High","gaps":["Allosteric coupling tested mainly on SUMO-1","Whether substrate identity tunes the allosteric response is unknown"]},{"year":2010,"claim":"Connected SENP1 to a hypoxia-responsive positive feedback loop by which HIF-1α transcribes SENP1 and SENP1 deSUMOylates/stabilizes HIF-1α, driving angiogenesis and later tumor stemness.","evidence":"ChIP, HRE promoter mutagenesis, siRNA, KO embryos, and xenografts across two studies","pmids":["20841360","28258134"],"confidence":"High","gaps":["SUMOylation site on HIF-1α driving stabilization not fully mapped here","Loop kinetics in normal vs cancer tissue differ in unresolved ways"]},{"year":2010,"claim":"Identified GATA1 as a direct SENP1 substrate controlling erythropoiesis, with deSUMOylation restoring GATA1 DNA binding and transcription.","evidence":"SENP1 conditional KO mice, in vitro deSUMOylation, ChIP, and bone marrow transplant; extended to CMS iPSC erythroid cells","pmids":["20457756","27821551"],"confidence":"High","gaps":["GATA1 SUMO site contribution to DNA binding mechanism partly inferred","Relative contributions of GATA1 vs Bcl-xL not fully separated"]},{"year":2008,"claim":"Established SENP1 as a redox- and cytokine-responsive enzyme that relocates from cytoplasm to nucleus, coupling stress signaling to deSUMOylation of nuclear substrates.","evidence":"Co-IP with thioredoxin, ROS-dependent release assays, catalytic mutant, siRNA, and KO MEFs","pmids":["18219322"],"confidence":"High","gaps":["Did not define the redox-sensitive residue (later C535/C683)","Generality of thioredoxin complex across cell types untested"]},{"year":2013,"claim":"Showed SENP1 controls oncogenic protein stability and activity by deSUMOylating substrates such as Pin1 and c-Myc, the latter altering its ubiquitination and phosphorylation.","evidence":"In vitro deSUMOylation, SUMO-site mutagenesis, catalytic C603S mutant, Co-IP, and ubiquitination assays","pmids":["23633483","30305424"],"confidence":"High","gaps":["Crosstalk hierarchy between deSUMOylation and ubiquitination not fully ordered","In vivo relevance of these axes in tumors not established here"]},{"year":2019,"claim":"Defined SENP1 as a metabolic-stress effector that translocates to mitochondria and activates Sirt3 by deSUMOylation, reprogramming mitochondrial acetylation across metabolism, T-cell memory, macrophage polarization, and kidney protection.","evidence":"In vitro deSUMOylation, SENP1 and Sirt3 KO/knock-in mice, mitochondrial fractionation, acetylation and metabolomic assays across multiple studies","pmids":["31302001","34272364","35417703","37608549"],"confidence":"High","gaps":["The mitochondrial import mechanism of a nuclear protease is not molecularly defined","AMPK-to-SENP1 signaling link is correlative in places"]},{"year":2015,"claim":"Identified SENP1 as a redox-gated amplifier of insulin exocytosis and as a NEMO deSUMOylase restraining NF-κB inflammation, linking it to diabetes pathophysiology.","evidence":"Islet- and adipocyte-specific SENP1 KO mice, patch-clamp exocytosis, NEMO K277/309 mutagenesis, human T2D islet rescue","pmids":["26389676","26596471"],"confidence":"High","gaps":["Distal exocytotic substrate(s) of SENP1 not molecularly identified","Tissue-of-origin for systemic phenotypes requires further dissection"]},{"year":2024,"claim":"Pinpointed the redox/metal chemistry that sets basal SENP1 activity, showing a C535 thiol with Zn2+ suppresses unrestrained exocytosis while reduced redox state activates it.","evidence":"C535 mutagenesis, β-cell- and pancreas-specific KO mice, patch-clamp, redox measurements, and glucose tolerance tests; complemented by C683 S-sulfhydration work","pmids":["38184650","36750014"],"confidence":"High","gaps":["How redox state is sensed upstream of C535 in vivo is incomplete","Whether C535 and C683 act independently is unresolved"]},{"year":2023,"claim":"Revealed SENP1 as a regulator of SUMO-driven liquid-liquid phase separation, removing SUMO to prevent RNF168 and MAVS condensation, thereby tuning DNA repair and antiviral signaling.","evidence":"In vitro LLPS reconstitution, SIM-motif mutagenesis, ubiquitination assays, NHEJ reporters, and Co-IP","pmids":["37350666","37188808"],"confidence":"High","gaps":["Generality of SENP1 control over phase separation across substrates unknown","Quantitative threshold of SUMO removal needed to dissolve condensates undefined"]},{"year":2021,"claim":"Linked SENP1 to a Mendelian neurodevelopmental disorder, showing a truncating mutation destabilizes FMRP and causes autistic-like deficits rescuable by region-specific SENP1 restoration.","evidence":"Human mutation identification, Senp1+/- mouse behavior and electrophysiology, FMRP SUMOylation/degradation assays, stereotaxic rescue","pmids":["34731627"],"confidence":"High","gaps":["Single human proband limits genetic generalization","How FMRP SUMOylation triggers degradation mechanistically is partial"]},{"year":null,"claim":"It remains unresolved how SENP1's broad substrate selectivity is achieved in vivo and how its nuclear, nuclear-pore, and mitochondrial localizations are coordinated across tissues and stress states.","evidence":"No single study in the timeline reconciles substrate targeting with the multi-compartment localization program","pmids":[],"confidence":"Low","gaps":["No global rule governs which substrate is engaged in which compartment","The molecular machinery for nuclear-to-mitochondrial translocation is undefined","Substrate prioritization under competing stress signals is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,5,9,17,30,32,43,44]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2,5]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[6,46,47]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,10,24,32]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[32,37,39,45]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,9,10,24]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[10,16,24,47]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[29,43]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[21,25,39,41,42,44]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,38,50]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[20,32,37,39]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[38,41,44]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[13]}],"complexes":["nuclear pore complex","TNF receptor signaling complex (TNF-RSC)"],"partners":["SUMO1","NUP153","THIOREDOXIN","HIF-1Α","GATA1","SIRT3","RIPK1","NEMO"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P0U3","full_name":"Sentrin-specific protease 1","aliases":["Sentrin/SUMO-specific protease SENP1"],"length_aa":644,"mass_kda":73.5,"function":"Protease that catalyzes two essential functions in the SUMO pathway (PubMed:10652325, PubMed:15199155, PubMed:15487983, PubMed:16253240, PubMed:16553580, PubMed:21829689, PubMed:21965678, PubMed:23160374, PubMed:24943844, PubMed:25406032, PubMed:29506078, PubMed:34048572, PubMed:37257451). The first is the hydrolysis of an alpha-linked peptide bond at the C-terminal end of the small ubiquitin-like modifier (SUMO) propeptides, SUMO1, SUMO2 and SUMO3 leading to the mature form of the proteins (PubMed:15487983). The second is the deconjugation of SUMO1, SUMO2 and SUMO3 from targeted proteins, by cleaving an epsilon-linked peptide bond between the C-terminal glycine of the mature SUMO and the lysine epsilon-amino group of the target protein (PubMed:15199155, PubMed:16253240, PubMed:21829689, PubMed:21965678, PubMed:23160374, PubMed:24943844, PubMed:25406032, PubMed:29506078, PubMed:34048572, PubMed:37257451). Deconjugates SUMO1 from HIPK2 (PubMed:16253240). Deconjugates SUMO1 from HDAC1 and BHLHE40/DEC1, which decreases its transcriptional repression activity (PubMed:15199155, PubMed:21829689). Deconjugates SUMO1 from CLOCK, which decreases its transcriptional activation activity (PubMed:23160374). Deconjugates SUMO2 from MTA1 (PubMed:21965678). Inhibits N(6)-methyladenosine (m6A) RNA methylation by mediating SUMO1 deconjugation from METTL3 and ALKBH5: METTL3 inhibits the m6A RNA methyltransferase activity, while ALKBH5 desumoylation promotes m6A demethylation (PubMed:29506078, PubMed:34048572, PubMed:37257451). Desumoylates CCAR2 which decreases its interaction with SIRT1 (PubMed:25406032). Deconjugates SUMO1 from GPS2 (PubMed:24943844)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9P0U3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SENP1","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SENP1","total_profiled":1310},"omim":[{"mim_id":"617842","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 1; PSMD1","url":"https://www.omim.org/entry/617842"},{"mim_id":"616182","title":"CHRONIC MOUNTAIN SICKNESS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/616182"},{"mim_id":"615708","title":"ZINC FINGER PROTEIN 451; ZNF451","url":"https://www.omim.org/entry/615708"},{"mim_id":"612845","title":"SENTRIN-SPECIFIC PROTEASE FAMILY, MEMBER 5; SENP5","url":"https://www.omim.org/entry/612845"},{"mim_id":"612157","title":"SENTRIN-SPECIFIC PROTEASE FAMILY, MEMBER 1; SENP1","url":"https://www.omim.org/entry/612157"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Focal adhesion sites","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"salivary gland","ntpm":30.5},{"tissue":"testis","ntpm":57.7}],"url":"https://www.proteinatlas.org/search/SENP1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9P0U3","domains":[{"cath_id":"3.40.395.10","chopping":"426-641","consensus_level":"medium","plddt":95.6322,"start":426,"end":641}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0U3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0U3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0U3-F1-predicted_aligned_error_v6.png","plddt_mean":60.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SENP1","jax_strain_url":"https://www.jax.org/strain/search?query=SENP1"},"sequence":{"accession":"Q9P0U3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P0U3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P0U3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0U3"}},"corpus_meta":[{"pmid":"28258134","id":"PMC_28258134","title":"SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop.","date":"2017","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/28258134","citation_count":194,"is_preprint":false},{"pmid":"31302001","id":"PMC_31302001","title":"SENP1-Sirt3 Signaling Controls Mitochondrial Protein Acetylation and Metabolism.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31302001","citation_count":191,"is_preprint":false},{"pmid":"26389676","id":"PMC_26389676","title":"Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells.","date":"2015","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/26389676","citation_count":158,"is_preprint":false},{"pmid":"15199155","id":"PMC_15199155","title":"SENP1 enhances androgen receptor-dependent transcription through desumoylation of histone deacetylase 1.","date":"2004","source":"Molecular and cellular 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practice","url":"https://pubmed.ncbi.nlm.nih.gov/36827886","citation_count":13,"is_preprint":false},{"pmid":"31249806","id":"PMC_31249806","title":"CDX2/mir-145-5p/SENP1 Pathways Affect LNCaP Cells Invasion and Migration.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31249806","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51261,"output_tokens":12972,"usd":0.174181,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":24182,"output_tokens":5282,"usd":0.12648,"stage2_stop_reason":"end_turn"},"total_usd":0.300661,"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\": 2003,\n      \"finding\": \"SENP1 is a nuclear-localized SUMO-specific cysteine protease; mutation of the N-terminal nuclear localization signal causes cytoplasmic accumulation; mutation of the active-site cysteine (dominant-negative) causes accumulation of high-molecular-weight SUMO-1 conjugates; the N-terminal regulatory domain suppresses constitutive catalytic activity of the core domain; SENP1 itself is a target for SUMO-1 modification at a nonconsensus site; SENP1 localization is influenced by SUMO-1-conjugated target proteins.\",\n      \"method\": \"Mutagenesis of NLS and catalytic cysteine, subcellular localization by imaging, immunoprecipitation, dominant-negative overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — active-site mutagenesis, NLS mutagenesis, localization experiments, and dominant-negative phenotype in a single focused study\",\n      \"pmids\": [\"14563852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SENP1 enhances androgen receptor (AR)-dependent transcription not by deSUMOylating AR itself, but by deconjugating SUMO from HDAC1, thereby reducing HDAC1 deacetylase activity; RNAi depletion of HDAC1 reduced SENP1's transcriptional enhancement effect.\",\n      \"method\": \"Transcriptional reporter assays, RNAi knockdown of HDAC1, co-immunoprecipitation, in vitro deSUMOylation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro deSUMOylation, RNAi epistasis, reporter assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15199155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SENP1 processes all SUMO-1, -2, and -3 precursors in vitro, with highest efficiency for SUMO-1 followed by SUMO-2 and SUMO-3; the catalytic domain alone determines substrate specificity; two residues immediately after the 'GG' region of SUMO precursors determine differential maturation efficiency.\",\n      \"method\": \"In vitro protease assay with purified recombinant SENP1, mutagenesis of SUMO precursor C-terminal fragments\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro cleavage assay with mutagenesis, single lab but multiple substrates tested\",\n      \"pmids\": [\"15487983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Retroviral insertional mutation of mouse SENP1/SuPr-2 increases steady-state levels of sumoylated proteins and causes placental abnormalities and embryonic lethality, demonstrating that deSUMOylation by SENP1 is essential for mammalian development.\",\n      \"method\": \"Retroviral insertional mutagenesis in mice, Western blot for SUMO conjugates, embryonic phenotyping\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in vivo with defined molecular phenotype (global hyperSUMOylation) and specific developmental readout\",\n      \"pmids\": [\"15923632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SENP1 deSUMOylates HIPK2 both in vitro and in cells; SENP1 contains a nuclear export sequence (NES) in its C-terminal region and shuttles between cytoplasm and nucleus; forced nuclear localization of SENP1 or NES mutation enhances HIPK2 deSUMOylation and induces dissociation of HIPK2 from nuclear bodies.\",\n      \"method\": \"In vitro deSUMOylation assay, NES mutagenesis, co-immunoprecipitation, subcellular localization imaging\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro assay plus cellular mutagenesis and localization, single lab\",\n      \"pmids\": [\"16253240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of SENP1 catalytic domain C603S mutant in complex with SUMO-1 at 2.8 Å resolution reveals that SENP1 requires a self-conformational change prior to peptide/isopeptide bond cleavage; four unique SENP1 residues facilitate SUMO-1 binding; SENP1 can also hydrolyze the thioester linkage in E1-SUMO and E2-SUMO intermediates.\",\n      \"method\": \"X-ray crystallography, in vitro protease activity assay with active-site mutant, structural comparison with SENP2\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro functional validation, reveals novel hydrolytic activity on E1/E2-SUMO thioesters\",\n      \"pmids\": [\"16712526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In resting endothelial cells, SENP1 resides in the cytoplasm complexed with thioredoxin; TNF stimulation releases SENP1 from thioredoxin in a ROS-dependent manner and induces SENP1 nuclear translocation; nuclear SENP1 deSUMOylates HIPK1, promoting its cytoplasmic translocation and ASK1-JNK activation leading to apoptosis; catalytic-inactive SENP1 mutant and siRNA of SENP1 block this pathway.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, catalytic mutant overexpression, SENP1-KO MEFs, subcellular fractionation/localization\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, catalytic mutant, siRNA, and KO MEF validation across multiple orthogonal methods\",\n      \"pmids\": [\"18219322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Among SENPs tested (1, 2, 3, 5, 6), only SENP1 and SENP2 efficiently cleave AR-SUMO-1 conjugates in intact cells and in vitro; androgens induce rapid SUMO-1 conjugation of AR; SENP1 reverses ligand-induced AR SUMOylation and promotes AR-dependent transcription in a catalytic activity-dependent and promoter-selective manner; SENP1 knockdown attenuates AR target gene expression and androgen-stimulated LNCaP cell growth.\",\n      \"method\": \"In vitro deSUMOylation assay, in-cell SUMOylation assay, siRNA knockdown, transcriptional reporter assay\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro assay, cellular knockdown, reporter assays, multiple SENPs compared, single lab\",\n      \"pmids\": [\"19116244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-6 induces SENP1 mRNA expression; SENP1 deSUMOylates PML, disrupting PML bodies and relieving PML-mediated suppression of STAT3 activation; catalytically inactive SENP1 fails to reverse PML suppression of STAT3.\",\n      \"method\": \"Co-immunoprecipitation, catalytic mutant, Western blot, STAT3 reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — single lab, catalytic mutant and Co-IP but limited mechanistic depth\",\n      \"pmids\": [\"18474224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SENP1 deSUMOylates GATA1 directly (demonstrated in vitro); SENP1 knockout mice develop anemia with fetal liver erythropoiesis defects; SUMOylated GATA1 accumulates in SENP1-KO livers and shows reduced DNA binding at GATA1-responsive gene promoters; GATA1-dependent gene expression and erythropoiesis are restored by SENP1-mediated deSUMOylation.\",\n      \"method\": \"SENP1 conditional knockout mice, in vitro deSUMOylation assay, bone marrow transplant, ChIP, Western blot\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic KO with defined erythropoiesis phenotype, in vitro reconstitution, ChIP, multiple orthogonal methods\",\n      \"pmids\": [\"20457756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HIF-1α is a direct transcriptional activator of SENP1 (via hypoxia response element on Senp1 promoter); SENP1 in turn deSUMOylates and stabilizes HIF-1α, forming a positive feedback loop; SENP1 silencing decreases VEGF production and endothelial cell angiogenic function; SENP1-null embryos show reduced vascular endothelial cells.\",\n      \"method\": \"ChIP, HRE promoter mutation, siRNA knockdown, angiogenesis assays, SENP1-KO embryo analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, promoter mutagenesis, siRNA, KO embryo analysis across multiple orthogonal methods\",\n      \"pmids\": [\"20841360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SENP1 overexpression in rheumatoid arthritis synovial fibroblasts decreases histone H4 acetylation at the MMP-1 promoter, reduces MMP-1 expression and invasiveness; this effect is dependent on HDAC4 accumulation at the MMP-1 promoter; SENP1 fails to modulate MMP-1 in HDAC4-silenced cells.\",\n      \"method\": \"SENP1 overexpression, siRNA knockdown of HDAC4, ChIP, RT-PCR, invasion assay\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ChIP, epistasis by HDAC4 siRNA, single lab with multiple methods\",\n      \"pmids\": [\"20079608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SENP1 overexpression in prostate cancer promotes HIF-1α stabilization, VEGF production, and angiogenesis; androgen-driven SENP1 transgene in mice induces high-grade prostatic intraepithelial neoplasia; SENP1 also enhances AR- and cyclin D1-dependent prostate epithelial cell proliferation.\",\n      \"method\": \"Transgenic mouse model, immunohistochemistry, cell proliferation assays, VEGF measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with defined molecular pathway, single lab\",\n      \"pmids\": [\"20551310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SENP1 and SENP2 are targeted to kinetochores in mitosis; SENP1 knockdown delays sister chromatid separation at metaphase; proper spatial and temporal control of sumoylation at kinetochores by SENP1 is required for chromosome segregation.\",\n      \"method\": \"siRNA knockdown, live-cell imaging, kinetochore targeting assays, chromosome segregation analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with specific mitotic phenotype, localization data, single lab\",\n      \"pmids\": [\"24048451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nup153 interacts with SENP1 through its N-terminal domain; SENP1 and SENP2 co-depletion increases sumoylation of endogenous Nup153; SENP1 levels are influenced by Nup153 abundance (whereas SENP2 is not), suggesting Nup153 anchors SENP1 at the nuclear pore complex.\",\n      \"method\": \"Co-immunoprecipitation, RNAi depletion, dominant-negative mutants, Western blot for SUMO conjugates\",\n      \"journal\": \"Nucleus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP and RNAi with substrate accumulation, single lab\",\n      \"pmids\": [\"22688647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SENP1 and SENP2 co-depletion causes mislocalization and reduced levels of multiple nucleoporins, revealing a role for pore-associated SENPs in nucleoporin homeostasis and nuclear pore complex configuration; transport is altered under these conditions.\",\n      \"method\": \"siRNA co-depletion, immunofluorescence, transport kinetics assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with localization and functional transport readout, single lab\",\n      \"pmids\": [\"24196834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SENP1 deficiency increases ER stress-induced apoptosis by accumulating SUMOylated XBP1; SENP1 directly deSUMOylates XBP1 and increases its transcriptional activity; XBP1 target genes are downregulated in SENP1-KO cells under ER stress.\",\n      \"method\": \"SENP1-KO cells, in vitro deSUMOylation assay, transcriptional reporter assay, Western blot\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells, in vitro assay, reporter assay, single lab\",\n      \"pmids\": [\"22370484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SENP1 binds to and deSUMOylates Pin1 on Lys6 (WW domain) and Lys63 (PPIase domain); Pin1 SUMOylation inhibits its isomerase activity and oncogenic function; SENP1-mediated deSUMOylation promotes Pin1 oncogenic activity (centrosome amplification, cell transformation) and increases Pin1 protein stability.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deSUMOylation assay, site-directed mutagenesis, cell transformation assay, centrosome amplification assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro assay, mutagenesis of SUMOylation sites, Co-IP, multiple functional readouts, single lab\",\n      \"pmids\": [\"23633483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SENP1 regulates mitochondrial gene expression via deSUMOylation of MEF-2C, which enhances MEF-2C-mediated PGC-1α transcription; SENP1 expression in cardiomyocytes is induced by hypertrophic stimuli through calcium/calcineurin-NFAT3; genetic induction of SENP1 leads to mitochondrial dysregulation and cardiac dysfunction.\",\n      \"method\": \"Cardiomyocyte SENP1 transgenic mouse, co-immunoprecipitation, Western blot, gene expression analysis\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model, Co-IP, pathway analysis, single lab\",\n      \"pmids\": [\"25446185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NMR relaxation measurements reveal that the β-grasp domain of SUMO-1 binding to SENP1's exosite induces structural changes ~20 Å away at the active site (including dynamics of 'lid' residue Trp465), allosterically activating the enzyme; this remote substrate-induced activation is required for efficient catalysis.\",\n      \"method\": \"NMR relaxation measurements, chemical shift perturbation, enzyme kinetic analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural study combined with enzyme kinetics in a single rigorous study\",\n      \"pmids\": [\"25263960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SENP1 is required for amplification of glucose-stimulated insulin exocytosis in pancreatic β-cells; the ICDc pathway generates NADPH, leading to glutathione (GSH) reduction, which activates SENP1 to amplify exocytosis at the distal exocytotic site; islet-specific Senp1 deletion in mice causes impaired glucose tolerance by reducing this amplification; the pathway is impaired in human T2D and can be rescued by SENP1 pathway intermediates.\",\n      \"method\": \"Islet-specific Senp1 KO mice, patch-clamp exocytosis measurements, glucose tolerance test, introduction of signaling intermediates into human T2D islets\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — islet-specific KO mice, human islet rescue experiments, patch-clamp, multiple orthogonal methods across labs\",\n      \"pmids\": [\"26389676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Adipocyte-specific deletion of SENP1 enhances SUMOylation of NEMO (NF-κB essential molecule) at lysine 277/309, leading to increased NF-κB activity, proinflammatory cytokine production, pancreatic inflammation and type-1 diabetes-like phenotype; NF-κB inhibitors reverse β-cell damage and T1DM phenotype in SENP1-deficient mice.\",\n      \"method\": \"Adipocyte-specific SENP1-KO mice, Co-IP, site-directed mutagenesis of NEMO K277/309, NF-κB reporter, cytokine measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO, site-specific mutagenesis, pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"26596471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Molecular dynamics simulations combined with the crystal structure show that SUMO1 β-grasp domain binding to the SENP1 exosite cleft allosterically activates SENP1 via a dock-and-coalesce mechanism: the β-grasp wedges open the exosite cleft, enabling docking of the SUMO C-terminus proximal portion, and strengthened cross-channel correlated motions allow the distal portion to coalesce at the catalytic center.\",\n      \"method\": \"Molecular dynamics simulation based on crystal structure, analysis of conformational and dynamic changes\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 (structural/computational) / Weak — computational study based on existing crystal structure, no independent wet-lab validation in this paper\",\n      \"pmids\": [\"27576863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Senp1 drives hypoxia-induced erythrocytosis via GATA1 and Bcl-xL; altering SENP1 levels in CMS iPSC-derived erythroid cells converts the CMS erythropoietic phenotype to non-CMS and vice versa; GATA1 is an essential downstream target of SENP1 in this context.\",\n      \"method\": \"iPSC technology, lentiviral SENP1 manipulation, erythroid differentiation assays, Western blot\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iPSC functional rescue/loss experiments, replicated GATA1 finding, single lab\",\n      \"pmids\": [\"27821551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SENP1 directly deSUMOylates HIF-1α, increasing its stability and transcriptional activity; HIF-1/2α directly transcribes SENP1 through hypoxia response elements; a positive feedback loop between SENP1 and HIF-1α drives hepatocellular carcinoma stemness under hypoxia.\",\n      \"method\": \"Immunoprecipitation for SUMO-HIF-1α, ChIP for HIF binding to SENP1 HRE, quantitative PCR, in vivo xenograft\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"28258134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SENP1 deSUMOylates PTP1B; in SENP1-deficient macrophages, highly SUMOylated PTP1B fails to de-phosphorylate STAT3, leading to STAT3 activation which induces SOCS3 and suppresses STAT1 signaling; this SENP1→PTP1B→STAT3→SOCS3 axis negatively regulates IFN-γ-STAT1-mediated M1 macrophage activation.\",\n      \"method\": \"SENP1-KO macrophages, Co-IP/SUMOylation assays, phospho-STAT Western blot, Listeria infection assay\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO macrophages with defined pathway readout, Co-IP, single lab\",\n      \"pmids\": [\"27702761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SENP1-modulated sumoylation regulates RB and Lamin A/C interaction; SUMO1 conjugation of both RB and Lamin A/C is required for their interaction; SENP1 removes SUMO1 from both proteins; this SUMO1-dependent RB-Lamin A/C complex protects both proteins from proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, SUMO site mutagenesis, proteasome inhibitor experiments, Western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, mutagenesis, proteasome assay, single lab\",\n      \"pmids\": [\"27270425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SENP1 deSUMOylates PTEN; in the absence of SENP1, SUMO1-modified PTEN is sequestered in the cytosol where it binds to SUMOylated WWP2 (E3 ubiquitin ligase), promoting PTEN ubiquitylation and degradation; SENP1 thereby blocks SUMO1-dependent ubiquitylation of PTEN.\",\n      \"method\": \"Co-immunoprecipitation, SUMOylation assays, SENP1 transgenic and KO cells, subcellular fractionation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, subcellular fractionation, SENP1 transgenic/KO models, single lab\",\n      \"pmids\": [\"27852060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Hypoxia triggers SENP1-mediated deSUMOylation of KLF15 in pulmonary endothelial cells, causing KLF15 translocation from nucleus to cytoplasm; nuclear KLF15 normally represses Arg2 transcription; SENP1-mediated KLF15 deSUMOylation therefore de-represses Arg2 (arginase 2), contributing to endothelial dysfunction.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, ChIP, SENP1 overexpression/knockdown, isolated pulmonary artery ring assay\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, functional vascular assay, single lab\",\n      \"pmids\": [\"29472234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Senp1 knockdown in nuclear pore complex (Nup153-depleted cells) displaces SENP1 from NPCs; artificial tethering of SENP1 to NPCs restores non-homologous end joining and 53BP1 sumoylation; proper NPC localization of SENP1 is required for 53BP1 SUMO1 modification and efficient NHEJ DNA repair.\",\n      \"method\": \"siRNA depletion, artificial tethering of SENP1 to NPC, NHEJ reporter assay, immunofluorescence, SUMO Western blot\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — NPC tethering rescue experiment, NHEJ reporter, single lab with multiple methods\",\n      \"pmids\": [\"28576968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SENP1 interacts with and deSUMOylates c-Myc in cells and in vitro; overexpression of wild-type but not catalytically inactive C603S SENP1 stabilizes c-Myc; SENP1-mediated deSUMOylation reduces c-Myc polyubiquitination, inhibiting proteasomal degradation; deSUMOylation promotes monoubiquitinated c-Myc and phosphorylation at S62 and T58.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deSUMOylation assay, catalytic mutant (C603S), siRNA knockdown, ubiquitination assay, Western blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution, catalytic mutant, Co-IP, ubiquitination assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30305424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Streptonigrin binds SENP1 at the SUMO-binding surface, disrupting SENP1-SUMO1 interaction; NMR identified binding site with key aromatic π-stacking interactions; streptonigrin treatment increases global SUMOylation and reduces HIF-1α levels in cells.\",\n      \"method\": \"NMR chemical shift perturbation, site-directed mutagenesis, global SUMOylation assay, HIF-1α Western blot\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR binding study with mutagenesis, single lab\",\n      \"pmids\": [\"29481054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SENP1 deSUMOylates Sirt3 in mitochondria; SUMOylation suppresses Sirt3 deacetylase activity; during fasting, SENP1 translocates into mitochondria and activates Sirt3 by deSUMOylation, leading to decreased acetylation of mitochondrial proteins and increased fatty acid oxidation; Sirt3 SUMOylation-deficient mutation reduces fat mass and antagonizes HFD-induced obesity.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deSUMOylation assay, SENP1-KO mice, Sirt3 SUMOylation mutant knock-in mice, subcellular fractionation, metabolic phenotyping\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro assay, KO mice, knock-in mutant mice, mitochondrial fractionation, multiple independent experiments\",\n      \"pmids\": [\"31302001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SENP1 deSUMOylates USP28; SUMOylation of USP28 in normoxia suppresses its deubiquitinase activity towards HIF-1α; hypoxia activates SENP1-mediated USP28 deSUMOylation, enhancing USP28 activity to accumulate HIF-1α, forming a SENP1-USP28-HIF-1α positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, in vivo deSUMOylation assay, luciferase reporter, in vitro deubiquitinase assay\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays (Co-IP, GST pulldown, in vitro assay), single lab\",\n      \"pmids\": [\"30622440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SENP1 deSUMOylates JAK2; deSUMOylation of JAK2 leads to its cytoplasmic accumulation and activation; the RUNX2-driven SENP1/JAK2 axis mediates platinum resistance in ovarian cancer; SENP1 inhibition or deficiency overcomes platinum resistance.\",\n      \"method\": \"Co-immunoprecipitation, SUMOylation assay, subcellular fractionation, siRNA/shRNA knockdown, platinum resistance assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, fractionation, functional drug resistance assay, single lab\",\n      \"pmids\": [\"33795649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SENP1 deSUMOylates IDOL (E3 ubiquitin ligase) at K293; IDOL SUMOylation counteracts its autoubiquitination and elevates IDOL protein levels; SENP1 overexpression increases LDLR protein levels and LDL uptake by removing IDOL SUMOylation; loss of SENP1 lowers LDLR in an IDOL-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, SUMOylation assay, SENP1 overexpression/knockdown, LDL uptake assay, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, functional LDL uptake assay, epistasis by IDOL, single lab\",\n      \"pmids\": [\"33154164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SENP1 deSUMOylates and stabilizes UBE2T; SENP1 knockout impairs HCC growth, migration and invasion; UBE2T overexpression or K8R (SUMOylation-deficient) mutation promotes cell growth and migration; the SENP1-UBE2T-Akt pathway mediates SENP1's carcinogenic activity.\",\n      \"method\": \"SENP1 KO cell model, Co-immunoprecipitation, deSUMOylation assay, UBE2T K8R mutagenesis, Akt signaling Western blot, in vivo xenograft\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KO cells, Co-IP, mutagenesis, in vivo model, single lab\",\n      \"pmids\": [\"31969492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Glucose limitation activates AMPK, which promotes SENP1-mediated Sirt3 deSUMOylation in T cell mitochondria; activated Sirt3 deacetylates mitochondrial metalloprotease YME1L1, suppressing its cleavage of OPA1 and facilitating mitochondrial fusion; this promotes T cell survival and memory development; fructose-1,6-bisphosphate (FBP) negatively regulates AMPK and suppresses the SENP1-Sirt3 axis.\",\n      \"method\": \"T cell-specific SENP1 and Sirt3 KO mice, co-immunoprecipitation, acetylation assays, mitochondrial morphology imaging, T cell memory assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple KO mouse models, Co-IP, acetylation assay, mitochondrial imaging, functional memory readout across orthogonal methods\",\n      \"pmids\": [\"34272364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SENP1 deSUMOylates RIPK1 within the TNF-R1 signaling complex (TNF-RSC); loss of SENP1 causes RIPK1 SUMOylation, re-orchestrates TNF-RSC, modulates RIPK1 ubiquitination patterns and activates RIPK1 kinase-dependent apoptosis; hepatocyte-specific SENP1-KO mice develop spontaneous NASH-related phenotypes reversed by RIPK1 kinase inhibition.\",\n      \"method\": \"Hepatocyte-specific SENP1-KO mice, Co-immunoprecipitation of TNF-RSC, RIPK1 SUMOylation/ubiquitination assays, genetic RIPK1 kinase inhibition rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO, TNF-RSC Co-IP, RIPK1 modification assays, genetic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"36414671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SENP1 promotes SENP1-Sirt3-GLUD1 axis in macrophages: SENP1 deSUMOylates Sirt3 to activate it; activated Sirt3 deacetylates GLUD1 (glutamate dehydrogenase 1), increasing its activity; increased GLUD1 activity promotes glutaminolysis and α-ketoglutarate accumulation, driving Jmjd3-dependent H3K27me3 demethylation and M2 macrophage polarization.\",\n      \"method\": \"SENP1-KO macrophages, co-immunoprecipitation, GLUD1 deacetylation assay, metabolomics, H3K27me3 ChIP\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO macrophages, Co-IP, enzymatic assay, metabolomics, ChIP, multiple orthogonal methods\",\n      \"pmids\": [\"35417703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"De novo heterozygous truncating mutation of SENP1 causes autistic-like symptoms in humans and mice; Senp1+/- mice show social deficits and repetitive behaviors with impaired inhibitory/excitatory synaptic function in the retrosplenial agranular (RSA) cortex; loss of SENP1 increases SUMOylation and degradation of FMRP; re-introduction of SENP1 or FMRP in the RSA fully rescues synaptic and behavioral deficits.\",\n      \"method\": \"Human genetic mutation identification, Senp1+/- mice behavioral and electrophysiology assays, FMRP SUMOylation/degradation assay, stereotaxic virus rescue in RSA\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human mutation, KO mouse phenotype, FMRP SUMOylation assay, region-specific in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"34731627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SENP1 deSUMOylates NEMO in microglia; overexpression of SENP1 inhibits IH-induced NEMO SUMOylation and NF-κB activation; SENP1-mediated NEMO deSUMOylation reduces neuroinflammation; siRNA-NEMO abolishes SENP1's protective effect, confirming NEMO as the relevant substrate.\",\n      \"method\": \"Co-immunoprecipitation, SUMOylation Western blot, siRNA epistasis for NEMO, NF-κB reporter assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, siRNA epistasis, single lab\",\n      \"pmids\": [\"34120412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SENP1 deSUMOylates KLF4; the SENP1-KLF4 axis promotes M1 macrophage polarization through NF-κB signaling; KLF4 SUMOylation deficiency (mirroring SENP1 activity) weakens tumor cell activity in co-culture.\",\n      \"method\": \"Co-immunoprecipitation, KLF4 SUMOylation assay, NF-κB reporter, macrophage polarization assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, functional polarization assay, single lab\",\n      \"pmids\": [\"35942612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SENP1 deSUMOylates RNF168; SUMOylated RNF168 undergoes liquid-liquid phase separation (LLPS), restricting its recruitment to DNA damage sites, reducing H2A ubiquitination, retaining 53BP1 in nuclear condensates, and impairing NHEJ; SENP1 prevents RNF168 LLPS by removing SUMO, promoting DNA repair and chemotherapy resistance.\",\n      \"method\": \"Co-immunoprecipitation, SUMOylation assay, in vitro LLPS assay, H2A ubiquitination assay, NHEJ reporter, siRNA/shRNA knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical and cell biology assays, in vitro LLPS, functional NHEJ readout, single lab\",\n      \"pmids\": [\"37350666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SENP1 deSUMOylates MAVS, inhibiting its PIAS3-induced poly-SUMOylation; poly-SUMOylation promotes K63-linked polyubiquitination and MAVS aggregation; SUMO conjugation enables MAVS phase separation through a newly identified SUMO-interacting motif (SIM) in MAVS; IRF3 is recruited to MAVS phase-separated droplets via a SIM in IRF3; IRF3 phosphorylation disables SIM-SUMO interactions, releasing activated IRF3.\",\n      \"method\": \"Co-immunoprecipitation, in vitro LLPS assay, ubiquitination assay, IRF3 phosphorylation assay, mutagenesis of MAVS/IRF3 SIM motifs\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reconstituted LLPS, Co-IP, mutagenesis, ubiquitination assays in one rigorous study\",\n      \"pmids\": [\"37188808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SENP1 deSUMOylates RIPK1 to inhibit apoptosis; SENP1 deSUMOylates Sirt3 in mitochondria during ischemia; AMPK activation by metformin promotes SENP1-Sirt3 axis, decreasing mitochondrial SOD2 acetylation, reducing mtROS, and protecting against acute kidney injury.\",\n      \"method\": \"AKI mouse models, Sirt3 SUMOylation site mutant knock-in (Sirt3 KR) mice, AMPK activation by metformin, metabolomics, Western blot for acetylated SOD2, Co-IP\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mutant mice, pharmacological AMPK activation, metabolomics, single lab\",\n      \"pmids\": [\"37608549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"H2S S-sulfhydrates SENP1 at C683, suppressing its protease activity; in diabetic cardiomyopathy, exogenous H2S S-sulfhydrates SENP1, increasing SERCA2a SUMOylation, improving SERCA2a expression and activity, calcium homeostasis and cardiomyocyte survival; SENP1 C683A mutant (non-sulfhydratable) abolishes these effects.\",\n      \"method\": \"SENP1 C683A mutagenesis, co-immunoprecipitation, SUMOylation assay, SERCA2a activity assay, calcium imaging, cardiac function measurement\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific mutagenesis, functional SERCA2a assay, Co-IP, single lab\",\n      \"pmids\": [\"36750014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SENP1 redox sensing in β-cells requires a thiol group at C535 which, together with Zn2+-binding, suppresses basal protease activity and unrestrained exocytosis; a more reduced cytosolic redox state after high-fat diet increases β-cell exocytosis in a SENP1-dependent manner; pancreas- and β-cell-specific SENP1 KO mice fail to upregulate exocytosis and become rapidly glucose intolerant after 2-day HFD.\",\n      \"method\": \"C535 mutagenesis, β-cell-specific and pancreas-specific SENP1 KO mice, patch-clamp exocytosis, redox measurements, glucose tolerance test\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — active-site mutagenesis, multiple tissue-specific KO models, patch-clamp, redox assay across multiple orthogonal methods\",\n      \"pmids\": [\"38184650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SENP1 deSUMOylates HDAC2; SENP1-mediated HDAC2 deSUMOylation enhances EGFR transcription and activates the AKT pathway in AML; IGF2BP3 binds the SENP1 3'-UTR in an m6A-dependent manner to upregulate SENP1 expression.\",\n      \"method\": \"Co-immunoprecipitation, SUMO assay, ChIP-qPCR, MERIP-qPCR, dual-luciferase reporter\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, ChIP, reporter assay, single lab\",\n      \"pmids\": [\"38822351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SENP1 deSUMOylates HSP90ab1 in cardiomyocytes; loss of SENP1 increases HSP90ab1 SUMOylation, leading to STAT3 activation and fibronectin secretion, which promotes fibroblast activation and cardiac fibrosis; mutation of HSP90ab1 Lys72 (SUMOylation site) or SENP1 overexpression ameliorates adverse ventricular remodeling after myocardial infarction.\",\n      \"method\": \"Cardiomyocyte-specific SENP1 KO and overexpression mice, Co-immunoprecipitation, HSP90ab1 K72 mutagenesis, cardiac function and fibrosis assessment\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO and OE mice, site mutagenesis, Co-IP, single lab\",\n      \"pmids\": [\"38992961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SENP1 deSUMOylates ACSL4, reducing its protein stability via removal of SUMO1; SENP1 inhibition in HNSCC increases ACSL4 SUMOylation and stabilization, promoting ferroptosis; SENP1 also regulates GPX4 expression to control ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation, Western blot for ACSL4 stability, ferroptosis assays (iron, MDA, GSH), shRNA knockdown\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, functional ferroptosis assay, single lab\",\n      \"pmids\": [\"38186303\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SENP1 is a nuclear/mitochondrial-localizing SUMO-specific cysteine protease (with redox-regulated activity at C535 and allosteric activation by the SUMO β-grasp domain) that deSUMOylates a broad range of substrates—including HIF-1α, GATA1, HDAC1, AR, c-Myc, Pin1, RIPK1, MAVS, RNF168, Sirt3, JAK2, NEMO, FMRP, KLF4, KLF15, IDOL, PTEN, UBE2T, p53, XBP1, HSP90ab1, ACSL4, PTP1B, and others—to regulate transcription, mitochondrial metabolism, DNA damage repair, innate immune signaling, erythropoiesis, insulin secretion, and cell death, with its mitochondrial translocation during metabolic stress (fasting, hypoxia) controlled via AMPK and with subcellular localization anchored at the nuclear pore complex through Nup153.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SENP1 is a SUMO-specific cysteine protease that both matures SUMO precursors and reverses SUMO conjugation on hundreds of substrates, thereby acting as a master regulator of transcription, metabolism, DNA repair, immune signaling, and cell death [#0, #2]. Catalytically, it processes SUMO-1, -2, and -3 precursors with its isolated catalytic domain dictating specificity, and it additionally hydrolyzes the thioester linkages of E1-SUMO and E2-SUMO intermediates; cleavage requires a substrate-induced conformational change in which binding of the SUMO \\u03b2-grasp domain to a distal exosite allosterically activates the active site ~20 \\u00c5 away [#2, #5, #19]. Its protease output is gated by redox and metal chemistry\\u2014a reactive thiol at C535 together with Zn2+ suppresses basal activity, and S-sulfhydration at C683 inhibits the enzyme\\u2014linking SENP1 activity to cellular redox state [#46, #47]. SENP1 is predominantly nuclear via an N-terminal NLS, shuttles through a C-terminal NES, and is anchored at the nuclear pore complex by Nup153, a localization required for 53BP1 SUMOylation and non-homologous end joining [#0, #4, #14, #29]; loss-of-function in mice causes global hyperSUMOylation, placental defects, and embryonic lethality, establishing deSUMOylation as essential for development [#3]. Functionally, SENP1 deSUMOylates and stabilizes HIF-1\\u03b1 in a hypoxia-driven positive feedback loop driving angiogenesis and tumor stemness [#10, #24], activates erythroid GATA1 to control erythropoiesis [#9, #23], and translocates into mitochondria upon AMPK activation during metabolic stress to deSUMOylate and activate Sirt3, reprogramming mitochondrial acetylation, fatty-acid oxidation, and immune-cell metabolism [#32, #37, #39]. It governs cell-death and inflammatory signaling by deSUMOylating RIPK1 within the TNF receptor complex, NEMO to restrain NF-\\u03baB, and MAVS to limit antiviral phase separation [#38, #41, #44], and it counteracts SUMO-driven liquid-liquid phase separation of RNF168 to promote DNA repair [#43]. A de novo heterozygous truncating SENP1 mutation causes autistic-like behavior by destabilizing FMRP, a phenotype rescued by restoring SENP1 in the retrosplenial cortex [#40].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established SENP1 as a nuclear SUMO-specific protease whose catalytic cysteine is required to reverse SUMO-1 conjugation and whose activity and localization are internally autoregulated.\",\n      \"evidence\": \"NLS and active-site cysteine mutagenesis with dominant-negative overexpression and localization imaging\",\n      \"pmids\": [\"14563852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define physiological substrates\", \"Regulatory-domain suppression mechanism not structurally resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the catalytic scope of SENP1, showing it both matures SUMO-1/-2/-3 precursors and that the catalytic domain alone confers substrate specificity.\",\n      \"evidence\": \"In vitro protease assays with recombinant SENP1 and SUMO precursor mutagenesis\",\n      \"pmids\": [\"15487983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro efficiencies may not reflect cellular substrate preference\", \"Did not address isopeptidase vs endopeptidase balance in cells\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that SENP1 deSUMOylation is essential for mammalian development, linking enzyme loss to global hyperSUMOylation in vivo.\",\n      \"evidence\": \"Retroviral insertional mutagenesis in mice with SUMO-conjugate Western blots and embryonic phenotyping\",\n      \"pmids\": [\"15923632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not pinpoint which substrate(s) drive lethality\", \"Insertional allele may be hypomorphic rather than null\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided the structural basis for catalysis, revealing a required self-conformational change and an unexpected ability to cleave E1/E2-SUMO thioesters.\",\n      \"evidence\": \"X-ray crystallography of the SENP1-SUMO1 catalytic complex with in vitro activity assays\",\n      \"pmids\": [\"16712526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Static structure did not capture the activation dynamics\", \"Physiological role of thioester hydrolysis not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved how substrate binding activates SENP1, showing the SUMO \\u03b2-grasp domain triggers allosteric activation at a remote active site.\",\n      \"evidence\": \"NMR relaxation and chemical-shift perturbation with enzyme kinetics, later supported by molecular dynamics\",\n      \"pmids\": [\"25263960\", \"27576863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Allosteric coupling tested mainly on SUMO-1\", \"Whether substrate identity tunes the allosteric response is unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected SENP1 to a hypoxia-responsive positive feedback loop by which HIF-1\\u03b1 transcribes SENP1 and SENP1 deSUMOylates/stabilizes HIF-1\\u03b1, driving angiogenesis and later tumor stemness.\",\n      \"evidence\": \"ChIP, HRE promoter mutagenesis, siRNA, KO embryos, and xenografts across two studies\",\n      \"pmids\": [\"20841360\", \"28258134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMOylation site on HIF-1\\u03b1 driving stabilization not fully mapped here\", \"Loop kinetics in normal vs cancer tissue differ in unresolved ways\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified GATA1 as a direct SENP1 substrate controlling erythropoiesis, with deSUMOylation restoring GATA1 DNA binding and transcription.\",\n      \"evidence\": \"SENP1 conditional KO mice, in vitro deSUMOylation, ChIP, and bone marrow transplant; extended to CMS iPSC erythroid cells\",\n      \"pmids\": [\"20457756\", \"27821551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GATA1 SUMO site contribution to DNA binding mechanism partly inferred\", \"Relative contributions of GATA1 vs Bcl-xL not fully separated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established SENP1 as a redox- and cytokine-responsive enzyme that relocates from cytoplasm to nucleus, coupling stress signaling to deSUMOylation of nuclear substrates.\",\n      \"evidence\": \"Co-IP with thioredoxin, ROS-dependent release assays, catalytic mutant, siRNA, and KO MEFs\",\n      \"pmids\": [\"18219322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the redox-sensitive residue (later C535/C683)\", \"Generality of thioredoxin complex across cell types untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed SENP1 controls oncogenic protein stability and activity by deSUMOylating substrates such as Pin1 and c-Myc, the latter altering its ubiquitination and phosphorylation.\",\n      \"evidence\": \"In vitro deSUMOylation, SUMO-site mutagenesis, catalytic C603S mutant, Co-IP, and ubiquitination assays\",\n      \"pmids\": [\"23633483\", \"30305424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk hierarchy between deSUMOylation and ubiquitination not fully ordered\", \"In vivo relevance of these axes in tumors not established here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined SENP1 as a metabolic-stress effector that translocates to mitochondria and activates Sirt3 by deSUMOylation, reprogramming mitochondrial acetylation across metabolism, T-cell memory, macrophage polarization, and kidney protection.\",\n      \"evidence\": \"In vitro deSUMOylation, SENP1 and Sirt3 KO/knock-in mice, mitochondrial fractionation, acetylation and metabolomic assays across multiple studies\",\n      \"pmids\": [\"31302001\", \"34272364\", \"35417703\", \"37608549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The mitochondrial import mechanism of a nuclear protease is not molecularly defined\", \"AMPK-to-SENP1 signaling link is correlative in places\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified SENP1 as a redox-gated amplifier of insulin exocytosis and as a NEMO deSUMOylase restraining NF-\\u03baB inflammation, linking it to diabetes pathophysiology.\",\n      \"evidence\": \"Islet- and adipocyte-specific SENP1 KO mice, patch-clamp exocytosis, NEMO K277/309 mutagenesis, human T2D islet rescue\",\n      \"pmids\": [\"26389676\", \"26596471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distal exocytotic substrate(s) of SENP1 not molecularly identified\", \"Tissue-of-origin for systemic phenotypes requires further dissection\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Pinpointed the redox/metal chemistry that sets basal SENP1 activity, showing a C535 thiol with Zn2+ suppresses unrestrained exocytosis while reduced redox state activates it.\",\n      \"evidence\": \"C535 mutagenesis, \\u03b2-cell- and pancreas-specific KO mice, patch-clamp, redox measurements, and glucose tolerance tests; complemented by C683 S-sulfhydration work\",\n      \"pmids\": [\"38184650\", \"36750014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How redox state is sensed upstream of C535 in vivo is incomplete\", \"Whether C535 and C683 act independently is unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed SENP1 as a regulator of SUMO-driven liquid-liquid phase separation, removing SUMO to prevent RNF168 and MAVS condensation, thereby tuning DNA repair and antiviral signaling.\",\n      \"evidence\": \"In vitro LLPS reconstitution, SIM-motif mutagenesis, ubiquitination assays, NHEJ reporters, and Co-IP\",\n      \"pmids\": [\"37350666\", \"37188808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of SENP1 control over phase separation across substrates unknown\", \"Quantitative threshold of SUMO removal needed to dissolve condensates undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked SENP1 to a Mendelian neurodevelopmental disorder, showing a truncating mutation destabilizes FMRP and causes autistic-like deficits rescuable by region-specific SENP1 restoration.\",\n      \"evidence\": \"Human mutation identification, Senp1+/- mouse behavior and electrophysiology, FMRP SUMOylation/degradation assays, stereotaxic rescue\",\n      \"pmids\": [\"34731627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single human proband limits genetic generalization\", \"How FMRP SUMOylation triggers degradation mechanistically is partial\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how SENP1's broad substrate selectivity is achieved in vivo and how its nuclear, nuclear-pore, and mitochondrial localizations are coordinated across tissues and stress states.\",\n      \"evidence\": \"No single study in the timeline reconciles substrate targeting with the multi-compartment localization program\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No global rule governs which substrate is engaged in which compartment\", \"The molecular machinery for nuclear-to-mitochondrial translocation is undefined\", \"Substrate prioritization under competing stress signals is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 5, 9, 17, 30, 32, 43, 44]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [6, 46, 47]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 10, 24, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005643\", \"supporting_discovery_ids\": [14, 15, 29]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [32, 37, 39, 45]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 9, 10, 24]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [10, 16, 24, 47]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [29, 43]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [21, 25, 39, 41, 42, 44]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 38, 50]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [20, 32, 37, 39]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [38, 41, 44]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\n      \"nuclear pore complex\",\n      \"TNF receptor signaling complex (TNF-RSC)\"\n    ],\n    \"partners\": [\n      \"SUMO1\",\n      \"Nup153\",\n      \"thioredoxin\",\n      \"HIF-1\\u03b1\",\n      \"GATA1\",\n      \"Sirt3\",\n      \"RIPK1\",\n      \"NEMO\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}