Affinage

SENP2

Sentrin-specific protease 2 · UniProt Q9HC62

Length
589 aa
Mass
67.9 kDa
Annotated
2026-06-10
74 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SENP2 is a SUMO-specific cysteine protease with dual catalytic functions: it matures SUMO-1/2/3 precursors and cleaves SUMO from conjugated substrates, with deconjugation kinetically favored over processing and Met497 acting as a determinant of SUMO isoform specificity, as defined by transition-state and substrate-complex crystal structures (PMID:15296745, PMID:17099700). Its localization is highly regulated: N-terminal elements tether SENP2 to the nucleoplasmic face of the nuclear pore complex through direct binding to Nup153, karyopherin-mediated FG-nucleoporin engagement, and contacts with the Nup107-160 subcomplex, an arrangement that restricts which nuclear SUMO conjugates it can access (PMID:11896061, PMID:22031293, PMID:22688647); an N-terminal amphipathic helix additionally directs SENP2 to ER, Golgi, and inner nuclear membranes, and the enzyme is also found in mitochondria (PMID:29874116, PMID:36708515). At the pore SENP2 maintains nucleoporin homeostasis and is recruited to kinetochores in mitosis, where its dosage governs chromosome congression (PMID:24048451, PMID:24196834). Through substrate deSUMOylation SENP2 controls a broad range of processes; recurring logic is that SUMOylation marks substrates for ubiquitin-dependent degradation or alters their localization/DNA binding, and SENP2 reverses this to stabilize or activate them — for example deSUMOylating and stabilizing C/EBPβ to drive adipogenesis and beige-fat programs (PMID:20194620, PMID:35196497), enabling ERRα DNA binding and UCP1-driven thermogenesis (PMID:40579429), promoting fatty-acid oxidation via PPARδ/γ (PMID:25784542), and clearing SUMO from MDC1 to favor NHEJ and radioresistance (PMID:30796017). In innate immunity and NF-κB signaling it deSUMOylates NEMO, IRF3, and IκBα to tune genotoxic and antiviral responses (PMID:21777808, PMID:22028379, PMID:31964975). SENP2 also regulates mitochondrial fission and metabolism through DRP1 and SDHA (PMID:35064188, PMID:36708515), neuronal excitability via Kv7.2/Kv7.3 channels (PMID:34509475), and stability of AMPKα, Akt, Smad4, and many other substrates (PMID:34971706, PMID:33687053, PMID:37301920). Its own activity is set post-translationally by p90RSK-mediated T368 phosphorylation that drives nuclear export, CHK1-mediated S344 phosphorylation favoring retention, CBP acetylation that inhibits activity, and USP44-mediated deubiquitination that stabilizes the protein (PMID:25689261, PMID:37711550, PMID:36708515, PMID:41250203).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 High

    Established that SENP2 is not a freely diffusible deSUMOylase but is spatially restricted, answering how a SUMO protease achieves substrate selectivity.

    Evidence Co-IP, in vivo localization, and N-terminal deletion mutants showing direct Nup153 binding at the NPC nucleoplasmic face

    PMID:11896061

    Open questions at the time
    • Did not define the full set of pore-tethering interactions
    • Did not identify physiological substrates restricted by pore association
  2. 2004 High

    Defined the catalytic basis of SENP2 by capturing protease-SUMO interaction, answering how the enzyme recognizes and acts on SUMO.

    Evidence X-ray structure of a covalent thiohemiacetal transition-state complex with SUMO-1 plus in vitro maturation/deconjugation assays and Gly-Gly mutants

    PMID:15296745

    Open questions at the time
    • Did not resolve kinetic preference between maturation and deconjugation
    • Isoform specificity determinants not yet mapped
  3. 2006 High

    Explained substrate-lysine positioning and SUMO isoform discrimination, answering why SENP2 prefers deconjugation and how it distinguishes SUMO paralogs.

    Evidence Multiple crystal structures of inactive SENP2 with RanGAP1-SUMO-1/2 and SUMO precursors, with Met497 mutagenesis and in vitro assays

    PMID:17099700

    Open questions at the time
    • Structural basis does not explain cellular substrate selection
    • No structure of full-length enzyme with regulatory N-terminus
  4. 2011 High

    Resolved the dynamic, multivalent mechanism of NPC tethering and showed it limits substrate access, refining how localization regulates SENP2 activity.

    Evidence FRAP, domain-deletion mutants, and Co-IP with karyopherins and the Nup107-160 subcomplex

    PMID:22031293

    Open questions at the time
    • Signals controlling release from the pore not fully defined
    • Quantitative substrate set gated by tethering unknown
  5. 2011 High

    Placed SENP2 in a genotoxic-stress negative-feedback loop, answering how SUMO dynamics on NEMO and IRF3 shape NF-κB and antiviral output.

    Evidence Co-IP, deSUMOylation assays, ChIP, and SENP2-null cells linking NEMO/IRF3 deSUMOylation to IKK/NF-κB and IFN-β responses

    PMID:21777808 PMID:22028379

    Open questions at the time
    • Crosstalk with other SENPs in the same loop incompletely resolved
    • In vivo immune consequences not addressed in these studies
  6. 2010 High

    Connected SENP2 to a transcription-factor stabilization logic, answering how deSUMOylation controls cell differentiation.

    Evidence siRNA knockdown, ubiquitination assays, and C/EBPβ overexpression rescue in adipogenesis

    PMID:20194620

    Open questions at the time
    • Whether SUMO-to-ubiquitin switch on C/EBPβ generalizes to other substrates not tested here
    • Upstream signals regulating SENP2 in adipocytes not defined
  7. 2018 High

    Expanded SENP2 localization beyond the pore to intracellular membranes, answering how the enzyme reaches non-nuclear compartments.

    Evidence In vitro membrane-binding assay, BioID interactome, amphipathic-helix mutants, and karyopherin-α regulation

    PMID:29874116

    Open questions at the time
    • Membrane-associated substrates only partially identified
    • Functional role of membrane targeting incompletely defined
  8. 2019 High

    Showed SENP2 protects substrates from RNF4-VCP-mediated SUMO-targeted degradation to direct DNA repair pathway choice, linking deSUMOylation to radioresistance.

    Evidence SUMOylation assays, focus-retention imaging, NHEJ/HR reporters, and RNF4-VCP epistasis on MDC1

    PMID:30796017

    Open questions at the time
    • Quantitative contribution to HR via free-SUMO provision not separated from direct MDC1 effect
    • Clinical relevance of 3q amplification in patients not established here
  9. 2021 High

    Established SENP2 as a regulator of mitochondrial dynamics, ion channels, and kinase stability, broadening its physiological reach to insulin secretion, neuronal excitability, and metabolism.

    Evidence Tissue-specific Senp2 knockout mice, SUMO/ubiquitination assays, electrophysiology, and rescue experiments across DRP1, Kv7.2/3, AMPKα, Akt, MEF2A, SMN, PLCβ4

    PMID:23224591 PMID:33687053 PMID:34465891 PMID:34509475 PMID:34628513 PMID:34971706 PMID:35064188

    Open questions at the time
    • Substrate prioritization in a given tissue not resolved
    • Whether single substrate accounts for each phenotype not always isolated
  10. 2022 High

    Refined the adipose and vascular roles into defined regulatory axes, answering how SENP2 controls thermogenesis and smooth-muscle phenotype.

    Evidence Adipocyte-specific KO mice, Co-IP, ChIP for the C/EBPβ-DAXX-HOXC10 axis, and myocardin K573 site mutagenesis

    PMID:35196497 PMID:36293488

    Open questions at the time
    • Tissue-specific substrate hierarchy not fully mapped
    • Some substrate links rest on single-lab evidence
  11. 2023 High

    Demonstrated mitochondrial and immune metabolic roles and identified acetylation as a brake on SENP2 activity, linking metabolic state to SUMO dynamics.

    Evidence Mitochondrial fractionation, in vitro deSUMOylation and acetylation assays for SDHA/CBP, and T cell-specific KO with Smad4 deSUMOylation in colitis

    PMID:36708515 PMID:37301920 PMID:37462038

    Open questions at the time
    • How acetylation, phosphorylation, and SUMOylation of SENP2 are integrated remains unresolved
    • Mitochondrial import mechanism not defined
  12. 2025 Medium

    Identified post-translational stabilization and a non-canonical proteolytic activity, expanding both regulation and substrate scope of SENP2.

    Evidence USP44 deubiquitination (Co-IP/CHX chase), CHK1 S344 phospho knock-in mice, NCOA4-OTUB1 stability assays, and in vitro α-synuclein cleavage

    PMID:37711550 PMID:40028275 PMID:40366738 PMID:41250203

    Open questions at the time
    • Non-SUMO proteolytic activity on α-synuclein rests on single-lab in vitro evidence
    • Integration of multiple PTM inputs on SENP2 activity not reconstituted

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the dozens of identified SENP2 substrates are selected and prioritized within a given cell type, and how localization and the layered PTM code (phosphorylation, acetylation, SUMOylation, ubiquitination) are integrated to set activity, remains unresolved.
  • No unified model of substrate selection across compartments
  • PTM crosstalk on SENP2 not reconstituted in vitro
  • Human disease links largely inferred from mouse models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0098772 molecular function regulator activity 4 GO:0016787 hydrolase activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005635 nuclear envelope 3 GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2 GO:0005739 mitochondrion 1 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-9609507 Protein localization 3 R-HSA-1640170 Cell Cycle 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-73894 DNA Repair 1
Partners
AMPKΑDRP1IRF3MDC1NCOA4NEMONUP153SMAD4
Complex memberships
kinetochorenuclear pore complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 SENP2 localizes to the nuclear face of nuclear pore complexes (NPCs) through its N-terminal domain, which directly binds Nup153, a nucleoporin on the nucleoplasmic face of the pore. Removal of the Nup153-interacting region alters the spectrum of SUMO-1 conjugates within the cell, suggesting NPC association restricts SENP2 activity to a subset of nuclear SUMOylated proteins. Co-immunoprecipitation, in vivo localization, N-terminal deletion mutants The Journal of biological chemistry High 11896061
2004 X-ray crystal structures of human SENP2 catalytic domain alone and as a covalent thiohemiacetal transition-state complex with SUMO-1 revealed the protease and substrate surfaces mediating interaction. SENP2 processes SUMO-1, SUMO-2, and SUMO-3 precursors (maturation) and deconjugates them from substrates, with activity dependent on residues C-terminal to the conserved Gly-Gly motif of SUMO. X-ray crystallography, in vitro biochemical maturation and deconjugation assays, SUMO tail-swap and Gly-Gly insertion mutants Structure High 15296745
2006 Crystal structures of catalytically inert SENP2 protease domain complexed with RanGAP1-SUMO-1, RanGAP1-SUMO-2, SUMO-2 precursor, and SUMO-3 precursor revealed a 90° kink near the scissile bond that directs the substrate lysine toward a protease surface optimized for lysine deconjugation. SENP2 residue Met497 was identified as a key determinant of SUMO isoform specificity; SENP2 catalyzes deconjugation more efficiently than processing. X-ray crystallography (multiple complex structures), mutagenesis, in vitro deconjugation/processing assays Nature structural & molecular biology High 17099700
2011 SENP2 dynamically associates with NPCs via multiple N-terminal elements: (1) a nuclear localization signal that tethers SENP2 to FG-repeat nucleoporins through karyopherins, (2) a domain that directly contacts the Nup107-160 subcomplex, and (3) a nuclear export signal. Disruption of these interactions increases SENP2 substrate accessibility in cells. FRAP (fluorescence recovery after photobleaching), domain-deletion mutants, Co-IP with karyopherins and Nup107-160 subcomplex, in vivo localization Molecular biology of the cell High 22031293
2011 SENP2 is the primary SUMO protease that associates with NEMO, deSUMOylates NEMO, and inhibits DNA damage-induced NF-κB activation. NF-κB transcriptionally induces SENP2 (and SENP1) in response to genotoxic stimuli via ATM-dependent histone methylation at SENP2 promoter κB regions, creating a negative feedback loop. SENP2-null cells show biphasic NEMO SUMOylation, sustained IKK/NF-κB activation, and higher resistance to DNA damage-induced cell death. Co-IP, deSUMOylation assay, SENP2-null cells, overexpression/knockdown, chromatin immunoprecipitation, promoter analysis Molecular cell High 21777808
2011 SENP2 deSUMOylates IRF3, which then undergoes K48-linked ubiquitination at the same sites (K70 and K87) used for SUMOylation, leading to proteasomal degradation. SUMOylation and K48-ubiquitination of IRF3 are competitive at these lysines. SENP2-deficient cells have elevated IRF3 SUMOylation, reduced ubiquitination/degradation, higher IFN-β production, and reduced viral replication. Overexpression, siRNA knockdown, site-directed mutagenesis (K70R/K87R), ubiquitination assays, SENP2-deficient cells Journal of molecular cell biology High 22028379
2010 SENP2 is required for adipogenesis by deSUMOylating and stabilizing C/EBPβ. SUMOylation of C/EBPβ promotes its ubiquitination and proteasomal degradation; SENP2 reverses this. SENP2 knockdown prevents adipocyte differentiation by reducing C/EBPβ protein levels (without affecting mRNA), leading to decreased PPARγ and C/EBPα expression. Overexpression of C/EBPβ rescues the SENP2-knockdown adipogenesis defect. siRNA knockdown, overexpression, in vivo preadipocyte implantation, ubiquitination assays, rescue experiments Molecular and cellular biology High 20194620
2012 Two distinct sites in Nup153 bind SENP2 and SENP1: the unique N-terminal domain and a specific region within the C-terminal FG-rich region of Nup153. Nup153 itself is a substrate for SUMOylation, and depletion of SENP1/SENP2 by RNAi or expression of dominant-negative mutants increases endogenous Nup153 SUMOylation. Unlike SENP1, SENP2 levels are not affected by changes in Nup153 abundance. Co-IP, RNAi, dominant-negative mutants, SUMOylation assays Nucleus Medium 22688647
2013 SENP1 and SENP2 are targeted to kinetochores during mitosis. SENP2 kinetochore targeting requires the Nup107-160 NPC subcomplex and is modulated by karyopherin α interactions. Overexpression of SENP2 (but not other SUMO isopeptidases) causes chromosome congression defects dependent on precise kinetochore targeting. RNAi knockdown of SENP1 (but not SENP2) delays sister chromatid separation at metaphase. Live-cell imaging, siRNA knockdown, overexpression, kinetochore targeting assays Molecular biology of the cell High 24048451
2013 SENP1 and SENP2 co-depletion causes mislocalization of many nucleoporins and in some cases reduces their levels, revealing a role for pore-associated SENPs in nucleoporin homeostasis and proper NPC configuration. Remaining NPCs retain transport capability but with altered kinetics. RNAi co-depletion, immunofluorescence, transport assays Molecular biology of the cell Medium 24196834
2013 SENP2 interacts with ERα via its N-terminal region (binding the hinge region of ERα) and represses ERα-mediated transcription independently of its SUMO protease activity through a transcriptional repressive domain in its N-terminus. This domain recruits HDAC3 to be fully active. SENP2 also represses estrogen-dependent and independent proliferation of MCF7 cells, requiring both its proteolytic and transcriptional repressive activities. GST pulldown, Co-IP, proximity ligation assay, reporter assays, siRNA, chromatin immunoprecipitation, deletion mutants Molecular endocrinology Medium 24422630
2015 Disturbed flow activates p90RSK, which phosphorylates SENP2 at threonine 368 (T368). T368 phosphorylation promotes nuclear export of SENP2, leading to decreased eNOS expression and increased pro-inflammatory adhesion molecule expression and apoptosis. In an atherosclerosis mouse model, EC-specific DN-p90RSK is protective, and SENP2 depletion abolishes this protective effect. In vivo kinase assay, phospho-mutant overexpression, nuclear fractionation, LDLR-deficient mouse model, EC-specific transgenic overexpression The Journal of clinical investigation High 25689261
2015 SENP2 promotes fatty acid oxidation in skeletal muscle by deSUMOylating PPARδ and PPARγ, which enhances their recruitment to promoters of FAO genes (CPT1b and ACSL1). Palmitate treatment induces NF-κB-mediated SENP2 upregulation. Muscle-specific SENP2 overexpression in mice increases FAO and alleviates high-fat diet-induced obesity and insulin resistance. ChIP, overexpression in myotubes, muscle-specific transgenic mice, FAO assays, siRNA Diabetes High 25784542
2018 SENP2 deSUMOylates SET domain bifurcated 1 (Setdb1). SUMOylation of Setdb1 promotes its occupancy at the Pparg and Cebpa gene promoters and suppresses their expression via H3K9me3 histone methylation. Adipocyte-specific Senp2 deficiency leads to accumulation of SUMOylated Setdb1, reduced Pparg/Cebpa expression, and decreased adipose lipid storage. Co-IP, ChIP, adipocyte-specific Senp2 knockout mice, SUMOylation assays Journal of molecular cell biology High 29272473
2018 SENP2 is targeted to intracellular membranes (ER, Golgi, inner nuclear membrane) via a predicted N-terminal amphipathic α-helix that directly binds membranes in vitro. Karyopherin-α binding to SENP2 regulates this membrane association. BioID proximity labeling confirmed interactions with ER, Golgi, and inner nuclear membrane-associated proteins. In vivo localization, in vitro membrane binding assay, BioID, karyopherin-α interaction studies, amphipathic helix mutants Molecular biology of the cell High 29874116
2019 SENP2 deSUMOylates MDC1 to prevent its excessive SUMOylation and subsequent RNF4-VCP-mediated clearance from DSBs, thereby promoting NHEJ. In homologous recombination (HR), SENP2 activity provides free SUMO. Increased SENP2 expression (as in chromosome 3q amplification) prolongs MDC1 focus retention, increases NHEJ efficiency, and promotes radioresistance. SUMOylation assays, focus retention imaging, NHEJ/HR reporter assays, SENP2 overexpression/knockdown, RNF4-VCP epistasis Genes & development High 30796017
2019 EBV oncoprotein LMP1 increases SUMOylation of SENP2 at K48 and K447 in a CTAR-dependent manner, decreases SENP2 activity, inhibits SENP2 ubiquitination, reduces SENP2 turnover, and alters SENP2 localization. Inhibition of ubiquitination alone is sufficient to mimic LMP1-induced changes in SENP2 activity and trafficking. SUMO modification assays, ubiquitination assays, localization imaging, LMP1 mutant analysis, site-directed mutagenesis (K48/K447) Scientific reports Medium 31266997
2019 SENP2 deSUMOylates TBL1/TBLR1, which prevents formation of complexes with β-catenin that facilitate β-catenin nuclear translocation. Through this mechanism, SENP2 suppresses MMP13 expression and inhibits bladder cancer cell migration and invasion. Co-IP, β-catenin nuclear fractionation, overexpression/knockdown, SUMOylation assays Scientific reports Medium 26369384
2019 SENP2 deSUMOylates TGF-β receptor I (TGF-βRI), thereby suppressing TGF-β signaling and TGF-β-induced epithelial-mesenchymal transition in bladder cancer cells. Co-IP, SUMOylation assays, overexpression/knockdown, in vivo tumor metastasis model Molecular carcinogenesis Medium 28574613
2019 SENP2 co-immunoprecipitates with and directly deSUMOylates OAT3 in rat kidney; SENP2 overexpression reduces OAT3 SUMOylation, expression, and transport activity in COS-7 cells, while SENP2 knockdown has opposite effects. A catalytic mutant of SENP2 does not affect OAT3. Co-IP from rat kidney, overexpression, siRNA knockdown, catalytic mutant, transport activity assay Biochimica et biophysica acta. Biomembranes Medium 31054272
2020 SENP2 silencing in multiple myeloma cells increases SUMO2-conjugated IκBα, leading to NF-κB activation and bortezomib resistance. SENP2 overexpression sensitizes cells to bortezomib by promoting IκBα deSUMOylation and suppressing NF-κB. siRNA knockdown, overexpression, SUMO2 conjugation assays (Co-IP), NF-κB reporter assay, drug sensitivity assay Scientific reports Medium 31964975
2021 SENP2 deSUMOylates DRP1 (a mitochondrial fission protein); SENP2 deficiency in pancreatic β cells increases SUMO2/3 conjugation to DRP1, suppresses DRP1 S616 phosphorylation, induces mitochondrial elongation and dysfunction, and impairs glucose-stimulated insulin secretion. SENP2 overexpression restores GSIS impairment caused by DRP1 knockdown. β cell-specific Senp2 knockout mice, SUMO conjugation assays, phospho-DRP1 Western blot, mitochondrial morphology imaging, GSIS assays, rescue overexpression Experimental & molecular medicine High 35064188
2021 SENP2 deSUMOylates AMPKα, promoting its ubiquitination and proteasomal degradation, thereby reducing AMPKα protein stability. Loss of hepatic SENP2 increases AMPKα stability, reduces gluconeogenesis, and protects against high-fat diet-induced hyperglycemia. AMPKα kinase inhibition reverses the effect of SENP2 deficiency on gluconeogenesis. Hepatic SENP2 knockout mice, Co-IP, in vitro deSUMOylation assay, ubiquitination assay, epistasis with AMPKα inhibitor, liver-specific adenoviral overexpression The Journal of biological chemistry High 34971706
2021 SENP2 deSUMOylates Akt; SENP2 deficiency increases Akt SUMOylation and kinase activity, decreases GSK3β levels, and promotes cardiomyocyte proliferation and angiogenesis, improving cardiac function after myocardial infarction. SENP2 expression increases during postnatal heart development. SENP2-deficient mice and cells, SUMOylation assays, Akt kinase assay, cardiomyocyte proliferation and MI model Clinical science Medium 33687053
2021 SENP2 deSUMOylates MEF2A; SENP2 is the major de-SUMOylation enzyme for MEF2A identified by an unbiased shRNA screen. SUMOylated MEF2A accumulates in SENP2-knockdown cells and SENP2-knockout embryos. SENP2 enhances MEF2A transcriptional activity directly via deSUMOylation, and SENP2 protein accumulates in response to activity-dependent stimuli to mediate activity-dependent MEF2A deSUMOylation. shRNA screen, in vivo SUMOylation assays, SENP2-knockout embryos, overexpression, activity-dependent stimulation Molecular biology reports Medium 23224591
2021 SENP2 deficiency in neurons leads to hyper-SUMOylation of Kv7.2 and Kv7.3 potassium channel subunits. Hyper-SUMOylated Kv7.2/Kv7.3 show reduced PIP2 binding and decreased interaction with CaM1, impairing CaM1-mediated channel assembly. Mutation of Kv7.2/Kv7.3 SUMOylation sites decreases CaM1 binding and enhances channel assembly. SENP2-deficient mice develop spontaneous seizures due to reduced M-currents, and also display elevated acetylcholine/increased vagal tone causing cardiac arrhythmias. SENP2-deficient mice, SUMOylation site mutagenesis, PIP2 binding assay, CaM1 Co-IP, electrophysiology (M-current recording), pharmacological rescue (atropine, vagotomy, retigabine) The Journal of biological chemistry High 34509475
2021 SENP2 deficiency causes hyper-SUMOylation of SMN protein (modified by SUMO2 with E3 ligase PIAS2α). SUMOylated SMN undergoes ubiquitin-proteasome degradation via UBA1 and E3 ligase ITCH. SUMOylation also increases SMN acetylation and inhibits Cajal body formation. SENP2-deficient mice develop SMA-like pathology with decreased muscle fibers and motor neurons. SENP2-deficient mouse model, SUMO assays, ubiquitination assays, co-IP, E3 ligase identification, Cajal body imaging Journal of molecular medicine High 34628513
2021 SENP2 deSUMOylates PLCβ4, preventing SUMO-dependent ubiquitin-mediated degradation catalyzed by PIAS2α and RNF4. SUMOylated PLCβ4 is transported to the nucleus via Nup205- and RanBP2-dependent pathways. SENP2-deficient mice show decreased PLCβ4, reduced IP3 formation, dysregulated intracellular calcium homeostasis, and defects in neurogenesis. Co-IP, SUMOylation assays, SENP2-deficient mice, calcium imaging, nuclear import assays, neurogenesis assays Cell death and differentiation High 34465891
2022 SENP2 deSUMOylates C/EBPβ; sumoylated C/EBPβ recruits the transcriptional repressor DAXX to suppress HOXC10 (a browning inhibitor) expression. Adipocyte-specific Senp2 knockout (Senp2-aKO) mice are resistant to diet-induced obesity due to increased thermogenic gene expression and beige adipocyte accumulation. SENP2 thus operates in a SENP2-C/EBPβ-HOXC10 axis that controls beige adipogenesis. Adipocyte-specific Senp2 KO mice, SUMOylation assays, Co-IP (DAXX recruitment), ChIP, energy expenditure measurements Cell reports High 35196497
2022 SENP2 promotes phenotypic switching of vascular smooth muscle cells by deSUMOylating myocardin at K573 (modified by SUMO-1 via E3 ligase PIAS4). SUMO-1 modification stabilizes myocardin, whereas SENP2-mediated deSUMOylation facilitates proteasome-dependent myocardin degradation. Co-IP, SUMOylation site mutagenesis (K573), overexpression, proteasome inhibitor assays, PIAS4 ligase identification, smooth muscle cell phenotype assays International journal of molecular sciences Medium 36293488
2023 SENP2 is present in mitochondria where it deSUMOylates SDHA (SUMOylated by PIAS3). SUMOylation of SDHA controls assembly and activity of the SDH complex. CBP acetyltransferase acetylates SENP2, negatively regulating its deSUMOylation activity. Under glutamine deprivation, decreased CBP levels activate SENP2, leading to SDHA deSUMOylation, dampened TCA cycle/ETC activity, and succinate accumulation to limit ROS and promote cancer cell survival. Co-IP, mitochondrial fractionation, in vitro deSUMOylation assay, acetylation assay, PIAS3 ligase identification, SDH activity assay, glutamine deprivation experiments Cell reports High 36708515
2023 SENP2 deSUMOylates SERCA2a; during myocardial ischemia/reperfusion injury (I/RI), SENP2 expression increases in the cytoplasm and promotes SERCA2a deSUMOylation, leading to calcium overload in cardiomyocytes. Inhibition of SENP2 (but not SENP1) reverses the I/RI-induced decline of SERCA2a SUMOylation, reduces infarct area, and improves cardiac function. Adenoviral overexpression/suppression, immunoprecipitation for SERCA2a SUMOylation, echocardiography, infarct staining, subcellular fractionation Chinese medical journal Medium 37462038
2023 SENP2 deSUMOylates Smad4, reducing its nuclear entry and suppressing Rorc expression, thereby restraining pathogenic Th17 differentiation. T cell-specific Senp2 deletion exacerbates experimental colitis with elevated GM-CSF+IL-17A+ pathogenic Th17 cells. Adoptive transfer experiments confirmed cell-autonomous function of SENP2 in Th17 restraint. T cell-specific Senp2 knockout mice, SUMOylation assay for Smad4, nuclear fractionation, adoptive transfer, colitis model Communications biology High 37301920
2019 SENP2 is required for SUMO2/SUMO3 regulation of placentation. SENP2 loss causes placental deficiencies linked to SUMO2/3 hyper-modification; reducing SUMO2 or SUMO3 gene dosage alleviates placental defects in SENP2 knockout mice, establishing genetic interaction between SENP2 and SUMO2/3 for trophoblast development. Genetic epistasis (SENP2 KO × SUMO2 or SUMO3 heterozygous mouse crosses), histology, embryonic phenotype analysis Developmental dynamics Medium 31625212
2018 SENP2 deSUMOylates NDR1 (STK38) at K465; SUMOylation of NDR1 attenuates its inhibition of p38/ERK1/2 activation by decreasing NDR1 association with MEK kinase 1/2. Low-level laser irradiation increases NDR1 SUMOylation by downregulating SENP2, leading to faster keratinocyte migration. Co-IP, SUMOylation site mutagenesis (K465), kinase activity assays, SENP2 overexpression/knockdown, keratinocyte migration assay FASEB journal Medium 29969578
2025 SENP2 deSUMOylates NCOA4 at SUMO1 sites K81, K343, and K600. SUMOylation enhances NCOA4 stability via interaction with the deubiquitinase OTUB1 (which directly deubiquitinates NCOA4). SENP2-mediated deSUMOylation disrupts NCOA4-OTUB1 interaction, reduces NCOA4 stability, and alleviates ferritinophagy-dependent ferroptosis in cardiomyocytes after MI/R injury. Co-IP, SUMOylation site mutagenesis (K81/K343/K600), NCOA4 stability assays, SENP2 overexpression/deletion, in vivo MI/R model Autophagy Medium 40366738
2025 SENP2 cleaves α-synuclein at its N-terminus (non-canonical proteolytic activity distinct from SUMO deconjugation). N-terminally truncated αSyn seeds released from pathological neurons promote SDS-resistant high-molecular oligomer formation in vitro. SENP2 inhibition suppresses αSyn aggregate formation and propagation in cultured neurons and mouse brains. In vitro protease assay with recombinant αSyn, oligomerization assay, SENP2 inhibition in neuronal models and in vivo mouse brain iScience Medium 40028275
2025 CHK1 kinase phosphorylates SENP2 at S344 under laminar flow conditions. S344 phosphorylation inhibits ERK5 and p53 SUMOylation, suppressing endothelial cell activation. A SENP2 S344A knock-in mutation (generated by CRISPR/Cas9) in mice increases EC inflammation, migration, proliferation, apoptosis, and fibrotic changes. Phospho-specific antibody generation, CRISPR/Cas9 knock-in mice (S344A), kinase assays, CHK1 inhibitor experiments Frontiers in cardiovascular medicine Medium 37711550
2025 USP44 deubiquitinase interacts with SENP2 and stabilizes it through deubiquitination, as shown by Co-IP and cycloheximide chase assays. Knockdown of SENP2 reduces the inhibitory effect of USP44 on ESCC cell migration and invasion. Co-IP, LC-MS, cycloheximide chase, ubiquitination analysis, siSENP2 epistasis Clinical epigenetics Medium 41250203
2029 SENP2 deSUMOylates ERRα; sumoylated ERRα cannot bind its DNA-binding site (ERRE) in the Ucp1 promoter. SENP2-mediated deSUMOylation of ERRα enables formation of ERRα/PGC1α/CREB/RNA Pol II transcriptional complex at the Ucp1 promoter following β3-adrenergic stimulation, inducing UCP1 expression and thermogenesis. Brown adipocyte-specific Senp2 KO mice show impaired cold-induced thermogenesis. Brown adipocyte-specific Senp2 KO mice, ChIP, SUMOylation assays, Ucp1 reporter assay, ERRE binding assay, β3-adrenergic stimulation experiments Experimental & molecular medicine High 40579429
2017 ORC2 SUMOylation is reversibly controlled by SUMO E3 ligase PIAS4 and deSUMOylase SENP2 at the G2/M phase. Depletion of PIAS4 or overexpression of SENP2 eliminates ORC2 SUMOylation, causing abnormal centromeric H3K4 methylation and genome endoreduplication/polyploidy. ORC2-SUMO2 fusion protein expression reduces polyploidy in SENP2-overexpressing cells. Co-IP, overexpression/siRNA knockdown, centromeric H3K4me ChIP, ploidy analysis by flow cytometry, ORC2-SUMO2 fusion rescue Oncotarget Medium 29050267

Source papers

Stage 0 corpus · 74 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Association of the human SUMO-1 protease SENP2 with the nuclear pore. The Journal of biological chemistry 203 11896061
2004 A basis for SUMO protease specificity provided by analysis of human Senp2 and a Senp2-SUMO complex. Structure (London, England : 1993) 167 15296745
2006 Structural basis for SENP2 protease interactions with SUMO precursors and conjugated substrates. Nature structural & molecular biology 123 17099700
2015 Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function. The Journal of clinical investigation 76 25689261
2011 SENP2 negatively regulates cellular antiviral response by deSUMOylating IRF3 and conditioning it for ubiquitination and degradation. Journal of molecular cell biology 73 22028379
2011 NF-κB induction of the SUMO protease SENP2: A negative feedback loop to attenuate cell survival response to genotoxic stress. Molecular cell 69 21777808
2010 Control of adipogenesis by the SUMO-specific protease SENP2. Molecular and cellular biology 66 20194620
2011 Enhanced desumoylation in murine hearts by overexpressed SENP2 leads to congenital heart defects and cardiac dysfunction. Journal of molecular and cellular cardiology 62 22155005
2015 SUMO-Specific Protease 2 (SENP2) Is an Important Regulator of Fatty Acid Metabolism in Skeletal Muscle. Diabetes 55 25784542
2011 The SUMO-specific isopeptidase SENP2 associates dynamically with nuclear pore complexes through interactions with karyopherins and the Nup107-160 nucleoporin subcomplex. Molecular biology of the cell 51 22031293
2019 The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms. Genes & development 46 30796017
2018 Senp2 regulates adipose lipid storage by de-SUMOylation of Setdb1. Journal of molecular cell biology 46 29272473
2013 SENP1 and SENP2 affect spatial and temporal control of sumoylation in mitosis. Molecular biology of the cell 46 24048451
2012 Two distinct sites in Nup153 mediate interaction with the SUMO proteases SENP1 and SENP2. Nucleus (Austin, Tex.) 38 22688647
2012 SENP2 regulates hepatocellular carcinoma cell growth by modulating the stability of β-catenin. Asian Pacific journal of cancer prevention : APJCP 38 23098437
2015 SENP2 regulates MMP13 expression in a bladder cancer cell line through SUMOylation of TBL1/TBLR1. Scientific reports 34 26369384
2013 Transcriptional repression of estrogen receptor α signaling by SENP2 in breast cancer cells. Molecular endocrinology (Baltimore, Md.) 30 24422630
2014 SENP2 regulated the stability of β-catenin through WWOX in hepatocellular carcinoma cell. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 29 24969559
2023 Mitochondrial SENP2 regulates the assembly of SDH complex under metabolic stress. Cell reports 28 36708515
2017 SENP2 suppresses epithelial-mesenchymal transition of bladder cancer cells through deSUMOylation of TGF-βRI. Molecular carcinogenesis 27 28574613
2022 SENP2 regulates mitochondrial function and insulin secretion in pancreatic β cells. Experimental & molecular medicine 25 35064188
2020 Silencing of SENP2 in Multiple Myeloma Induces Bortezomib Resistance by Activating NF-κB Through the Modulation of IκBα Sumoylation. Scientific reports 25 31964975
2013 The SUMO proteases SENP1 and SENP2 play a critical role in nucleoporin homeostasis and nuclear pore complex function. Molecular biology of the cell 25 24196834
2019 The Epstein-Barr Virus Oncoprotein, LMP1, Regulates the Function of SENP2, a SUMO-protease. Scientific reports 24 31266997
2018 SENP2 alleviates CCl4-induced liver fibrosis by promoting activated hepatic stellate cell apoptosis and reversion. Toxicology letters 24 29535048
2019 SENP2 suppresses NF-κB activation and sensitizes breast cancer cells to doxorubicin. European journal of pharmacology 23 30940449
2022 SENP2 suppresses browning of white adipose tissues by de-conjugating SUMO from C/EBPβ. Cell reports 22 35196497
2021 Inhibition of SENP2-mediated Akt deSUMOylation promotes cardiac regeneration via activating Akt pathway. Clinical science (London, England : 1979) 22 33687053
2018 SUMO-specific protease 2 (SENP2) functions as a tumor suppressor in osteosarcoma via SOX9 degradation. Experimental and therapeutic medicine 21 30542495
2019 SENP2 Suppresses Necdin Expression to Promote Brown Adipocyte Differentiation. Cell reports 20 31433978
2021 The protease SENP2 controls hepatic gluconeogenesis by regulating the SUMOylation of the fuel sensor AMPKα. The Journal of biological chemistry 16 34971706
2018 SENP1 and SENP2 regulate SUMOylation of amyloid precursor protein. Heliyon 16 29862363
2021 SENP2-PLCβ4 signaling regulates neurogenesis through the maintenance of calcium homeostasis. Cell death and differentiation 15 34465891
2018 SUMO-specific protease 2 (SENP2) suppresses keratinocyte migration by targeting NDR1 for de-SUMOylation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15 29969578
2022 SENP2 Promotes VSMC Phenotypic Switching via Myocardin De-SUMOylation. International journal of molecular sciences 14 36293488
2018 SENP2 exerts an anti‑tumor effect on chronic lymphocytic leukemia cells through the inhibition of the Notch and NF‑κB signaling pathways. International journal of oncology 14 30431078
2016 Genetic Polymorphism of SUMO-Specific Cysteine Proteases - SENP1 and SENP2 in Breast Cancer. Pathology oncology research : POR 14 27178176
2023 SENP2-mediated SERCA2a deSUMOylation increases calcium overload in cardiomyocytes to aggravate myocardial ischemia/reperfusion injury. Chinese medical journal 13 37462038
2014 Engineering pre-SUMO4 as efficient substrate of SENP2. Protein engineering, design & selection : PEDS 13 24671712
2025 SENP2-mediated deSUMOylation of NCOA4 protects against ferritinophagy-dependent ferroptosis in myocardial ischemia-reperfusion injury. Autophagy 12 40366738
2022 Identification of Natural Products as SENP2 Inhibitors for Targeted Therapy in Heart Failure. Frontiers in pharmacology 12 35431915
2022 Discovery of a Dual SENP1 and SENP2 Inhibitor. International journal of molecular sciences 12 36292935
2021 The SUMO-specific protease SENP2 plays an essential role in the regulation of Kv7.2 and Kv7.3 potassium channels. The Journal of biological chemistry 12 34509475
2021 Regulation of Serotonin 1A Receptor SUMOylation by SENP2 and PIASxα. International journal of molecular sciences 12 34947973
2019 The requirement of SUMO2/3 for SENP2 mediated extraembryonic and embryonic development. Developmental dynamics : an official publication of the American Association of Anatomists 12 31625212
2012 SENP2 regulates MEF2A de-SUMOylation in an activity dependent manner. Molecular biology reports 12 23224591
2023 SENP2 restrains the generation of pathogenic Th17 cells in mouse models of colitis. Communications biology 10 37301920
2021 SENP2 Reduces Hepatocellular Carcinoma Stemness and Improves Sorafenib Sensitivity Through Inactivating the AKT/GSK3β/CTNNB1 Pathway. Frontiers in oncology 10 34950583
2018 The SUMO-specific isopeptidase SENP2 is targeted to intracellular membranes via a predicted N-terminal amphipathic α-helix. Molecular biology of the cell 9 29874116
2024 SENP2 promotes ESCC proliferation through SETDB1 deSUMOylation and enhanced fatty acid metabolism. Heliyon 8 39071660
2016 Senp2 expression was induced by chronic glucose stimulation in INS1 cells, and it was required for the associated induction of Ccnd1 and Mafa. Islets 8 27644314
2021 Hyper-SUMOylation of SMN induced by SENP2 deficiency decreases its stability and leads to spinal muscular atrophy-like pathology. Journal of molecular medicine (Berlin, Germany) 7 34628513
2020 Forebrain excitatory neuron-specific SENP2 knockout mouse displays hyperactivity, impaired learning and memory, and anxiolytic-like behavior. Molecular brain 7 32290845
2024 Extracellular vesicle-mediated regulation of imatinib resistance in chronic myeloid leukemia via the miR-629-5p/SENP2/PI3K/AKT/mTOR axis. Hematology (Amsterdam, Netherlands) 6 39056503
2024 SUMO1 modification of 0N4R-tau is regulated by PIASx, SENP1, SENP2, and TRIM11. Biochemistry and biophysics reports 6 39286522
2024 MicroRNA-145-5p inhibits the tumorigenesis of breast cancer through SENP2-regulated ubiquitination of ERK2. Cellular and molecular life sciences : CMLS 6 39578257
2023 Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition. Frontiers in cardiovascular medicine 6 37711550
2019 The SUMO-Specific Protease Senp2 Regulates SUMOylation, Expression and Function of Human Organic Anion Transporter 3. Biochimica et biophysica acta. Biomembranes 6 31054272
2024 SENP2-NDR2-p21 axis modulates lung cancer cell growth. European journal of pharmacology 5 38908669
2020 Cardiomyocyte-specific deletion of Senp2 contributes to CVB3 viral replication and inflammation. International immunopharmacology 5 33182061
2023 A polypeptide derived from pilose antler ameliorates CUMS-induced depression-like behavior by SENP2-PLCβ4 signaling axis. European journal of pharmacology 4 38056617
2020 Comprehensive in silico analysis for identification of novel candidate target genes, including DHX36, OPA1, and SENP2, located on chromosome 3q in head and neck cancers. Head & neck 4 33006201
2017 Reversible regulation of ORC2 SUMOylation by PIAS4 and SENP2. Oncotarget 4 29050267
2023 SENP2 knockdown in human adipocytes reduces glucose metabolism and lipid accumulation, while increases lipid oxidation. Metabolism open 3 37013149
2017 A Generic Protocol for Purifying Disulfide-Bonded Domains and Random Protein Fragments Using Fusion Proteins with SUMO3 and Cleavage by SenP2 Protease. Methods in molecular biology (Clifton, N.J.) 3 28470603
2015 A novel robust quantitative Förster resonance energy transfer assay for protease SENP2 kinetics determination against its all natural substrates. Molecular bioSystems 3 26486594
2024 Sumo-regulatory SENP2 controls the homeostatic squamous mitosis-differentiation checkpoint. Cell death & disease 2 39152119
2025 SENP2 as a critical regulator in liver ischemia-reperfusion injury. The international journal of biochemistry & cell biology 1 39890015
2025 SENP2-based N-terminal truncation of α-synuclein in Lewy pathology propagation. iScience 1 40028275
2025 SENP2 regulates UCP1-dependent thermogenesis in brown adipocytes via deSUMOylation of ERRα. Experimental & molecular medicine 1 40579429
2025 Hypermethylated USP44 deubiquitinates SENP2: a critical mechanism in esophageal cancer progression and a new target for intervention. Clinical epigenetics 1 41250203
2026 ETS1 targets the SENP2/HSPA8/FUNDC1 axis to ameliorate bronchopulmonary dysplasia by inhibiting mitochondrial damage-induced autophagy. Archives of biochemistry and biophysics 0 42069287
2026 Hepatic Senp2 deletion resolves the angiogenic switch in fibrosis via β-catenin/LECT2. Biochemical and biophysical research communications 0 42235328
2024 SENP2 negatively regulates RIG-I/MDA5 mediated innate immunity in black carp. Fish & shellfish immunology 0 39724728

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