{"gene":"USP13","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2011,"finding":"USP13 deubiquitinates Beclin1, and Beclin1 in turn controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. USP13 (with USP10) targets the Beclin1 subunit of Vps34 PI3 kinase complexes; inhibition of USP13 promotes degradation of Vps34 complexes. Because USP10 mediates deubiquitination of p53, Beclin1 regulation of USP13/USP10 activity connects p53 levels to autophagy.","method":"Small-molecule inhibitor (spautin-1) targeting USP10/USP13, Co-IP, protein stability assays in cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional assays, inhibitor + genetic knockdown, multiple orthogonal methods, widely replicated","pmids":["21962518"],"is_preprint":false},{"year":2011,"finding":"USP13 deubiquitinates MITF (microphthalmia-associated transcription factor), stabilizing MITF protein levels. Knockdown of USP13 leads to loss of MITF protein without affecting mRNA, demonstrating post-translational stabilization. USP13 modulates MITF downstream target gene expression and is required for melanoma growth.","method":"shRNA library screen against DUBs, USP13 knockdown, protein stability assays, in vivo nude mouse xenograft","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — shRNA screen plus functional validation, multiple assays in single lab","pmids":["21811243"],"is_preprint":false},{"year":2011,"finding":"USP13 regulates Siah2 E3 ubiquitin ligase stability and activity via its ubiquitin-binding domains (UBA and UBP domains) rather than its catalytic isopeptidase activity. USP13 binds ubiquitinated Siah2 and prevents its autodegradation, but this effect is abolished by mutations in ubiquitin-binding sequences, not catalytic site mutations. Consequently, USP13 attenuates Siah2's ability to target its substrates (PHD3, Spry2).","method":"Overexpression, shRNA knockdown, site-directed mutagenesis of catalytic and ubiquitin-binding domains, protein stability assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis distinguishing catalytic vs. non-catalytic mechanism, multiple constructs tested in single lab","pmids":["21659512"],"is_preprint":false},{"year":2011,"finding":"USP13 exhibits weak deubiquitinating activity preferring K63-linked polyubiquitin, operating in a non-activation manner. The ZnF domain of USP13, unlike that of its paralog USP5, cannot bind free ubiquitin and therefore USP13 cannot be activated by free ubiquitin. Substitution of the USP13 ZnF domain with the USP5 ZnF domain confers catalytic activation. The tandem UBA domains preferentially bind K63-linked diubiquitin, explaining the substrate preference.","method":"Biochemical DUB assays with K48/K63 polyubiquitin substrates, NMR structural analysis of ZnF domain, domain-swap mutagenesis, cell-based CD3δ regulation assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assay + NMR structure + mutagenesis, single lab with multiple orthogonal methods","pmids":["22216260"],"is_preprint":false},{"year":2013,"finding":"USP13 physically associates with PTEN and deubiquitinates PTEN to stabilize its protein levels. Loss of USP13 in breast cancer cells promotes AKT phosphorylation, proliferation, anchorage-independent growth, and glycolysis through downregulation of PTEN.","method":"DUB screen (30 DUBs) for PTEN physical association, Co-IP, in vitro deubiquitination assay, USP13 knockdown/overexpression, in vivo xenograft","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — screen + Co-IP + in vitro deubiquitination assay + in vivo, widely replicated across subsequent studies","pmids":["24270891"],"is_preprint":false},{"year":2014,"finding":"USP13 is a gp78-associated deubiquitinase that removes ubiquitin conjugates from Ubl4A (a component of the Bag6 chaperone complex), preventing gp78-mediated polyubiquitination and irreversible proteolytic inactivation of Bag6. This maintains the functionality of the Bag6 chaperone complex in ERAD, sharpening substrate specificity for the gp78 E3 ligase.","method":"Co-IP identifying USP13 association with gp78, in vitro ubiquitination/deubiquitination assays, cell-based ERAD substrate degradation assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution/in vitro assay + Co-IP + functional ERAD assay, multiple orthogonal methods in single publication","pmids":["24424410"],"is_preprint":false},{"year":2016,"finding":"USP13 deubiquitinates and stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination of c-Myc, thereby maintaining glioblastoma stem cell (GSC) self-renewal and tumorigenic potential. Depletion of USP13 promotes c-Myc ubiquitination and degradation. The ubiquitin-insensitive T58A-c-Myc mutant rescues the effects of USP13 disruption or FBXL14 overexpression.","method":"Co-IP, ubiquitination assays, USP13 knockdown/overexpression, T58A-c-Myc rescue experiments, in vivo tumor growth assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP + ubiquitination assay + genetic epistasis via rescue mutant, multiple orthogonal methods","pmids":["27923907"],"is_preprint":false},{"year":2016,"finding":"USP13 specifically deubiquitinates and upregulates ATP citrate lyase (ACLY) and oxoglutarate dehydrogenase (OGDH), two key metabolic enzymes determining mitochondrial respiration, glutaminolysis, and fatty acid synthesis in ovarian cancer cells.","method":"Co-IP, deubiquitination assays, knockdown/overexpression with metabolic readouts, in vivo ovarian tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP + deubiquitination assay + functional metabolic assays, multiple orthogonal methods single lab","pmids":["27892457"],"is_preprint":false},{"year":2017,"finding":"USP13 interacts with STING and deconjugates polyubiquitin chains from STING, preventing the recruitment of TBK1 to the STING signaling complex and thereby negatively regulating antiviral responses. USP13 knockout mice are more resistant to lethal HSV-1 infection.","method":"Co-IP identifying USP13-STING interaction, in vitro deubiquitination assay, USP13 KD/KO cells and knockout mice, IRF3/NF-κB activation assays, viral replication assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP + deubiquitination assay + KO mice + mechanistic TBK1 recruitment assay, multiple orthogonal methods","pmids":["28534493"],"is_preprint":false},{"year":2017,"finding":"USP13 is phosphorylated by ATM kinase following DNA damage, which facilitates its localization to DNA double-strand breaks (DSBs). USP13 then deubiquitinates RAP80, promoting RAP80 recruitment and proper DNA damage response (DDR) including BRCA1 complex foci formation.","method":"Co-IP, phosphorylation assays, DSB localization by immunofluorescence, RAP80 ubiquitination assays, USP13 depletion/inhibition sensitivity assays in ovarian cancer cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — phosphorylation-localization-deubiquitination axis with multiple assays, single lab","pmids":["28569838"],"is_preprint":false},{"year":2018,"finding":"USP13 interacts with and stabilizes MCL1 via deubiquitination, regulating MCL1 turnover in lung and ovarian cancer cells. CRISPR/Cas9-mediated USP13 depletion reduces MCL1 protein abundance and increases sensitivity to BH3 mimetic inhibitors.","method":"Unbiased siRNA screen, Co-IP, deubiquitination assay, CRISPR/Cas9 KO, in vivo xenograft, BH3 mimetic sensitivity assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA screen + Co-IP + deubiquitination assay + CRISPR KO, independently replicated (also confirmed in cervical cancer PMID 33627786)","pmids":["29335437"],"is_preprint":false},{"year":2018,"finding":"USP5 and USP13 are recruited to heat-induced stress granules via their deubiquitylating activities. Depletion of USP13 elevates ubiquitin chain levels in stress granules, accelerates their assembly, and markedly impairs their disassembly after heat stress removal. USP13 regulates stress granule dynamics by deubiquitylating protein-conjugated ubiquitin chains.","method":"Immunofluorescence recruitment assay, siRNA knockdown, ubiquitin chain level measurements, stress granule assembly/disassembly kinetics","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization to stress granules with functional depletion phenotype, single lab","pmids":["29567855"],"is_preprint":false},{"year":2020,"finding":"The E3 ubiquitin ligase NEDD4-1 undergoes K29-linked auto-ubiquitination at K1279, which serves as a scaffold to recruit USP13. The resulting NEDD4-1–USP13 complex deubiquitinates VPS34/PIK3C3 by removing K48-linked poly-ubiquitin chains at K419, stabilizing VPS34 and promoting autophagy initiation.","method":"Co-IP, deubiquitination assay, ubiquitin linkage-specific analysis, NEDD4-1 and USP13 KO cell lines, autophagosome formation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro deubiquitination + Co-IP + site-specific ubiquitin mapping + KO functional assay, multiple orthogonal methods","pmids":["32101753"],"is_preprint":false},{"year":2020,"finding":"USP13 interacts with cohesin and its ubiquitin-binding domains (UBA1/2) are required for this interaction. The interaction occurs specifically in the soluble nuclear fraction and preferentially during DNA replication. USP13 is paradoxically required for both deubiquitination and ubiquitination of cohesin subunits, and is required for dissociation of cohesin from chromatin as cells transit through mitosis, but is dispensable for sister chromatid cohesion.","method":"Endogenous dual-affinity purification + mass spectrometry, Co-IP in multiple cell lines, domain mapping (UBA1/2 mutants), CRISPR KO, cell fractionation, mitotic chromosome spreads","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal affinity purification/MS + domain mapping + CRISPR KO + multiple cell lines, single lab with multiple orthogonal methods","pmids":["33334891"],"is_preprint":false},{"year":2020,"finding":"USP13 associates with Aurora B kinase and stabilizes Aurora B, especially before mitotic entry. Aurora B-mediated phosphorylation of USP13 at Serine 114 promotes their association. USP13 instigates Aurora B deubiquitination and/or protects it from degradation in a manner that may be partially non-catalytic. Modulation of USP13 levels/activity affects unperturbed cell-cycle progression.","method":"Co-IP, phosphorylation assays, USP13 gain/loss-of-function, protein stability assays, cell cycle analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + phosphorylation mapping + functional cell-cycle assays, non-catalytic mechanism partially inferred, single lab","pmids":["32772043"],"is_preprint":false},{"year":2020,"finding":"USP13 deubiquitinates and stabilizes Smad4 in lung fibroblast cells. USP13 and Smad4 co-localize in the cytoplasm and co-translocate to the nucleus in response to TGF-β1. USP13 deficiency in mice reduces extracellular matrix (ECM) protein levels, demonstrating a role in ECM expression regulation through Smad4 stabilization.","method":"Co-IP, pulse-chase protein stability assay, USP13 KO mice, overexpression/knockdown, immunofluorescence co-localization","journal":"Translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + stability assay + KO mice, single lab with multiple methods","pmids":["32434004"],"is_preprint":false},{"year":2019,"finding":"USP13 deubiquitinates and stabilizes IL-1R8/Sigirr, an anti-inflammatory receptor. USP13 levels directly correlate with IL-1R8/Sigirr; knockdown increases IL-1R8/Sigirr poly-ubiquitination and degradation, enhancing TLR4 signaling and cytokine release. USP13-deficient mice are highly susceptible to LPS- and Pseudomonas-induced lung injury, and IL-1R8/Sigirr overexpression rescues the inflammatory phenotype.","method":"Receptor ligation chase model, Co-IP, poly-ubiquitination assay, USP13 KO mice, acute lung injury model, IL-1R8/Sigirr overexpression rescue","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mice + Co-IP + ubiquitination assay + genetic rescue, multiple orthogonal methods","pmids":["31204278"],"is_preprint":false},{"year":2021,"finding":"USP13 binds to TopBP1 and stabilizes it via deubiquitination, facilitating ATR activation in response to replication stress. Depletion of USP13 impedes ATR activation and hypersensitizes cells to replication stress-inducing agents.","method":"Co-IP, deubiquitination assay, USP13 knockdown, ATR activation assays, replication stress sensitivity assays","journal":"DNA repair","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + deubiquitination assay + functional ATR assay, single lab","pmids":["33592542"],"is_preprint":false},{"year":2021,"finding":"USP13 interacts with Snail transcription factor and deubiquitinates it, stabilizing Snail protein and promoting EMT and metastasis in gastric cancer. USP13 knockdown promotes Snail degradation blockable by proteasome inhibitor MG132; Snail knockdown blocks USP13-induced migration.","method":"Co-IP, deubiquitination assay, proteasome inhibitor rescue, knockdown/overexpression, migration/invasion assays","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + deubiquitination + MG132 rescue + epistasis, single lab","pmids":["34872023"],"is_preprint":false},{"year":2021,"finding":"USP13 deubiquitinates and stabilizes Mcl-1 in cervical cancer cells. USP13 depletion reduces Mcl-1 expression, inhibits cell proliferation, and increases sensitivity to BH3 mimetic ABT-263.","method":"Co-IP, deubiquitination assay, USP13 knockdown, Mcl-1 stability assays, BH3 mimetic sensitivity","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + deubiquitination assay + functional phenotype, single lab","pmids":["33627786"],"is_preprint":false},{"year":2021,"finding":"USP13 deubiquitinates IRAK4 in macrophages. Myeloid-specific USP13 deficiency increases LPS-induced pro-inflammatory responses and worsens septic symptoms in mice, which can be rescued by IRAK4 inhibitor co-administration.","method":"USP13 myeloid-specific KO mice (USP13MKO), Co-IP/deubiquitination assay, IRAK4 inhibitor rescue, BMDM inflammatory assays, sepsis mouse model","journal":"Microbes and infection","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice + deubiquitination assay + pharmacological rescue, single lab","pmids":["34298177"],"is_preprint":false},{"year":2022,"finding":"USP13 binds ZHX2 (Zinc Fingers And Homeoboxes 2) and promotes ZHX2 deubiquitination and protein stability in an enzymatically dependent manner. USP13 depletion leads to ZHX2 downregulation and decreased ccRCC cell proliferation.","method":"DUB cDNA library binding screen, Co-IP, deubiquitination assay, USP13 depletion, 2D/3D growth assays, in vivo tumor growth","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cDNA library screen + Co-IP + deubiquitination assay + in vivo, single lab","pmids":["36037364"],"is_preprint":false},{"year":2022,"finding":"N6-methyladenosine (m6A) modification by METTL3 (read by IGF2BP2) stabilizes USP13 mRNA. USP13 protein interacts with ATG5 and stabilizes ATG5 via deubiquitination; PAK1 kinase-mediated phosphorylation of ATG5 enhances its interaction with USP13. This USP13-ATG5 axis enhances autophagy and imatinib resistance in GIST cells.","method":"Co-IP, deubiquitination assay, PAK1 phosphorylation assay, m6A-seq, USP13 inhibitor (spautin-1) + 3-MA treatment in xenograft models","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + deubiquitination + phosphorylation assay + in vivo, single lab with multiple methods","pmids":["36528756"],"is_preprint":false},{"year":2022,"finding":"Casein kinase 2 (CK2) directly interacts with USP13 and phosphorylates it at Thr122, promoting the stability of USP13 protein. Thr122 phosphorylation is important for ovarian cancer cell proliferation.","method":"Co-IP, kinase assay, phospho-specific detection, phosphorylation-deficient and phosphomimetic mutants, cell proliferation assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + kinase assay + phosphomutant functional analysis, single lab","pmids":["36612196"],"is_preprint":false},{"year":2022,"finding":"USP13 modulates the stability of the APC/C adaptor CDH1. USP13 binds CDH1 and its overexpression increases CDH1 levels while depletion decreases them, establishing a USP13-CDH1-Aurora B regulatory axis for cell cycle progression.","method":"Co-IP, Western blot after USP13 overexpression/siRNA/shRNA, cell cycle analysis","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP + protein level change, no direct deubiquitination assay for CDH1, single lab single method","pmids":["35397714"],"is_preprint":false},{"year":2023,"finding":"USP13 deubiquitinates and stabilizes cyclin D1 by physically binding to its N-terminal domain and removing K48-linked (but not K63-linked) polyubiquitin chains, promoting G1/S cell cycle progression and proliferation in gastric cancer cells.","method":"Co-IP, deubiquitination assay with K48/K63 ubiquitin mutants, USP13 KO/overexpression, cell cycle analysis, in vivo xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro deubiquitination assay + domain binding + K-specific ubiquitin mutants + in vivo validation, multiple orthogonal methods","pmids":["37311811"],"is_preprint":false},{"year":2023,"finding":"USP13 directly binds p62/SQSTM1 and removes ubiquitin at Lys7 (K7) of the PB1 domain. This deubiquitination enhances p62 protein stability and facilitates p62 oligomerization, resulting in increased selective autophagy and degradation of Keap1, thereby promoting Nrf2 activation and antioxidant gene expression.","method":"Co-IP, site-directed mutagenesis (K7), ubiquitination assay, autophagy flux assays, Keap1/Nrf2 pathway readouts","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + site-specific mutagenesis + functional pathway assay, single lab","pmids":["37776917"],"is_preprint":false},{"year":2023,"finding":"USP13 interacts with and deubiquitinates METTL3 at K488 by removing K48-linked ubiquitin chains, stabilizing METTL3 and increasing global m6A abundance in osteosarcoma cells, which promotes ATG5 mRNA stability and autophagy-associated malignancy.","method":"Co-IP, deubiquitination assay with K48 ubiquitin mutants, RNA-seq, m6A-IP sequencing, USP13 inhibitor in xenograft","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + deubiquitination + multiomics + in vivo, single lab","pmids":["37151889"],"is_preprint":false},{"year":2023,"finding":"USP13 interacts with Twist1 and specifically cleaves K48-linked polyubiquitin chains from Twist1 induced by FBXL14, stabilizing Twist1 and promoting breast cancer cell migration and invasion. Twist1 in turn inhibits USP13 transcriptional activity, forming a negative feedback loop.","method":"Co-IP, GST pulldown, deubiquitination assay with K48-specific ubiquitin, USP13 KD/OE, migration/invasion and in vivo lung metastasis assays, luciferase reporter for USP13 promoter","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pulldown + K48-specific deubiquitination assay + in vivo, single lab","pmids":["36732432"],"is_preprint":false},{"year":2023,"finding":"KRAS drives expression of USP13 through the transcription factor RREB1. Elevated USP13 removes K63-linked polyubiquitination of β-catenin at lysine 508, enhancing binding of β-catenin to TCF4 and promoting KRAS-mutant NSCLC metastasis.","method":"ChIP/reporter assays for RREB1-USP13 axis, Co-IP, K63-specific deubiquitination assay, K508 site mutation, metastasis assays in vitro and in vivo","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional axis + site-specific deubiquitination + functional metastasis assays, single lab","pmids":["38043062"],"is_preprint":false},{"year":2023,"finding":"USP13 interacts with and deubiquitinates SARM1 (axon degeneration executor). USP13 deubiquitination of SARM1 increases the inhibitory interaction between SARM1's N-terminal ARM domain and C-terminal TIR domain, suppressing SARM1 activation and delaying injury-induced axon degeneration. Enzyme-dead USP13 fails to protect injured axons.","method":"Proximity labeling/proteomics to identify SARM1 interactome, overexpression of WT vs. enzyme-dead USP13, domain interaction assays, axon degeneration assays","journal":"Life medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics + enzymatic dead mutant + domain interaction assay + functional axon assay, single lab","pmids":["39872893"],"is_preprint":false},{"year":2023,"finding":"USP13 deubiquitinates Beclin 1 (distinct from the earlier finding that Beclin1 regulates USP13). In aged Usp13-deficient mice, impaired Beclin 1 deubiquitination leads to insufficient autophagic activity and increased vulnerability to bleomycin-induced lung fibrosis.","method":"USP13-deficient aged mice, Beclin 1 deubiquitination assay, Beclin 1 overexpression rescue, bleomycin fibrosis model","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice + deubiquitination assay + genetic rescue, single lab","pmids":["36150040"],"is_preprint":false},{"year":2020,"finding":"USP13 protein is degraded in response to LPS in Kupffer cells via the ubiquitin-proteasome system. LPS increases USP13 polyubiquitination and reduces its protein stability (not transcription). Inhibition of c-Jun N-terminal kinase (JNK) attenuates USP13 degradation, indicating JNK-dependent new protein synthesis is necessary for USP13 degradation. A catalytically inactive USP13 shows similar degradation, indicating the mechanism is activity-independent.","method":"LPS treatment, proteasome/lysosome inhibitor experiments, JNK inhibitor, cycloheximide chase, catalytic mutant USP13","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological inhibitors + catalytic mutant + stability assays, single lab","pmids":["33169399"],"is_preprint":false},{"year":2022,"finding":"USP13 deubiquitinates and stabilizes ATG5 in gastrointestinal stromal tumor cells (also confirmed in AML). PAK1-mediated phosphorylation of ATG5 enhances the ATG5-USP13 interaction.","method":"Co-IP, deubiquitination assay, PAK1 inhibition, USP13 knockdown, autophagy flux and tumor growth assays","journal":"Cell death and differentiation / Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + deubiquitination + phosphorylation assay, replicated in two cancer types (PMID 36528756, 39216303)","pmids":["36528756","39216303"],"is_preprint":false},{"year":2024,"finding":"USP13 interacts with and deubiquitinates NFE2L2/NRF2, upregulating NRF2 protein levels. In KRAS-mutant lung adenocarcinoma, USP13 depletion promotes an autophagy-to-ferroptosis switch through the NRF2-SQSTM1/p62-KEAP1 axis.","method":"DUB screen (85 DUBs), Co-IP, deubiquitination assay, USP13 KD in vitro and xenograft, autophagy/ferroptosis markers","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — screen + Co-IP + deubiquitination + in vivo, single lab","pmids":["39360581"],"is_preprint":false},{"year":2024,"finding":"USP13 interacts with TAK1 (transforming growth factor β-activated kinase 1) and inhibits K63-linked ubiquitination and phosphorylation of TAK1, thereby dampening downstream inflammatory pathways (NF-κB) and promoting insulin signaling in the context of NAFLD.","method":"Co-IP, ubiquitination assay (K63-specific), TAK1 inhibitor rescue, USP13 overexpression/KO mice, NAFLD models","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + K63-specific ubiquitination assay + KO mice + pharmacological rescue, single lab","pmids":["39033101"],"is_preprint":false},{"year":2024,"finding":"USP13 deubiquitinates ATG7 (autophagy-related 7) by preventing its degradation, stabilizing ATG7 protein and promoting ferroptosis in chicken granulosa cells.","method":"USP13 overexpression/knockdown, Co-IP, deubiquitination assay, ferroptosis markers (GSH, lipid peroxidation, iron)","journal":"Poultry science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP + single deubiquitination assay, non-mammalian model (chicken), single lab","pmids":["39214053"],"is_preprint":false},{"year":2023,"finding":"USP13 interacts with FASN (fatty acid synthase) and enhances FASN protein stability, with this USP13-FASN axis required for SCLC cancer stem cell maintenance and lipogenesis. Effect requires enzymatic activity of USP13 (inactive mutant cannot rescue).","method":"Co-IP, protein stability assay, WT vs. inactive USP13 rescue, sphere formation assay, in vivo tumor growth","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + inactive-mutant rescue + in vivo, single lab","pmids":["35898882"],"is_preprint":false},{"year":2021,"finding":"USP13 selectively stabilizes mutant EGFR (but not wild-type EGFR) in a peptidase-independent manner by counteracting the action of Cbl family E3 ubiquitin ligases.","method":"Unbiased high-throughput siRNA screen, USP13 KD, Cbl ligase functional assays, mutant vs. WT EGFR stability, in vitro and in vivo sensitivity assays","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA screen + functional Cbl epistasis + mutant specificity assay, single lab; non-catalytic mechanism supported by peptidase-independence","pmids":["33210294"],"is_preprint":false},{"year":2025,"finding":"USP13 stabilizes NLRP3 independently of its deubiquitinating enzyme activity by competing with E3 ligase TRIM31 to interact with NLRP3, preventing TRIM31-mediated ubiquitination of NLRP3 at K192 and K496, thereby inhibiting proteasomal degradation of NLRP3 and promoting NLRP3 inflammasome assembly and activation.","method":"Co-IP, ubiquitination assay with site-specific NLRP3 K192/K496 mutants, USP13 KO in human and mouse macrophages, DUB-dead mutant analysis, inflammasome activation readouts, peritonitis mouse model","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-specific mutagenesis + DUB-dead mutant + KO in two species + in vivo model, multiple orthogonal methods","pmids":["41004574"],"is_preprint":false},{"year":2025,"finding":"USP13 deubiquitinates STAT1, reducing its degradation. In cardiomyocytes, USP13 promotes STAT1-targeted Nppb gene transcription and enhances mitochondrial function. Cardiomyocyte-specific Usp13 knockout aggravates pressure overload-induced cardiac hypertrophy, while AAV9-mediated USP13 overexpression has therapeutic effects.","method":"Interactome analysis identifying STAT1 as substrate, Co-IP, deubiquitination assay, cardiomyocyte-specific KO mice (TAC/Ang II models), AAV9 overexpression","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — interactome + Co-IP + deubiquitination assay + tissue-specific KO + therapeutic rescue, multiple orthogonal methods","pmids":["40593642"],"is_preprint":false},{"year":2025,"finding":"USP13 deubiquitinates the stimulator of interferon genes (STING) and promotes its autolysosome-related degradation (rather than stabilization), alleviating cardiomyocyte inflammation in doxorubicin-induced cardiotoxicity. Cardiomyocyte-specific USP13 KO exacerbates cardiotoxicity while overexpression mitigates it.","method":"RNA-seq, Co-IP, deubiquitination assay, cardiomyocyte-specific KO mice, AAV9 overexpression, autophagy flux assays","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + deubiquitination + KO mice + AAV rescue, single lab; note: contrasts with PMID 28534493 where USP13 stabilizes STING in innate immunity; context-dependent","pmids":["40487656"],"is_preprint":false},{"year":2025,"finding":"USP13 deubiquitinates SMAD3 by removing K48-linked ubiquitin chains at K13 of SMAD3's MH2 domain (USP13 C345 is the catalytic cysteine involved), stabilizing SMAD3 and enhancing its transcriptional activity for profibrotic genes, thereby promoting hepatic stellate cell activation and liver fibrosis.","method":"Co-IP/MS substrate identification, domain mapping (MH2 domain), K13 site-specific ubiquitination assay, C345 catalytic mutant, HSC-specific AAV-mediated KD, CCl4 and BDL fibrosis mouse models","journal":"Hepatology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS + site-specific assay + catalytic mutant + in vivo KD, single lab","pmids":["40719972"],"is_preprint":false},{"year":2025,"finding":"USP13 deubiquitinates WWP1 E3 ligase by removing K29- and K48-linked polyubiquitin chains, stabilizing WWP1 via the ubiquitin-proteasome pathway. The transcription factor YY1 activates USP13 transcription and also upregulates WWP1 through USP13.","method":"Co-IP, mass spectrometry, ubiquitination assay with K29/K48-specific chains, ChIP and luciferase assay for YY1-USP13 promoter interaction, in vivo xenograft","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS + K-specific ubiquitination assay + ChIP/luciferase, single lab","pmids":["40319251"],"is_preprint":false},{"year":2025,"finding":"USP13 deubiquitinates NLRP3 at K557 by removing K63-linked ubiquitin chains, inhibiting NLRP3-ASC interaction and ASC polymerization, thereby inhibiting NLRP3 inflammasome activation and alleviating pyroptosis in cardiomyocytes in diabetic cardiomyopathy.","method":"Co-precipitation + LC-MS/MS substrate identification, K557 site-specific ubiquitination assay, K63-specific ubiquitin chains, cardiomyocyte-specific KO mice (type I and II diabetic), AAV9 overexpression, NLRP3-deficient rescue","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — LC-MS/MS + site-specific K63 deubiquitination + KO mice in two diabetic models + genetic rescue, multiple orthogonal methods","pmids":["41206387"],"is_preprint":false},{"year":2025,"finding":"USP13 stabilizes ACLY (ATP citrate lyase) via K48-specific deubiquitination at K726, preventing proteasomal degradation. Under hypoxia, HIF-1α transcriptionally upregulates USP13 by binding its promoter, creating a hypoxia-USP13-ACLY axis that drives ferroptosis resistance and immune evasion in HCC.","method":"Co-IP, K48-specific deubiquitination assay at K726, HIF-1α ChIP/promoter assay, USP13 inhibitor (2-Met) in PDOs and xenograft, scRNA-seq, flow cytometry","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + site-specific deubiquitination + ChIP + multiple models, single lab","pmids":["41330897"],"is_preprint":false},{"year":2025,"finding":"USP13 interacts with ALDOA (fructose-bisphosphate aldolase A) via its USP domain and regulates K48-linked deubiquitination and stability of ALDOA at K13, preventing its proteasomal degradation and thereby restraining ferroptosis in cardiomyocytes following myocardial infarction.","method":"Co-IP, K48-specific ubiquitination assay at K13, USP13-deficient mice + cardiac-specific AAV9 overexpression, MI surgery model, ferroptosis markers","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + site-specific deubiquitination + KO mice + AAV overexpression, single lab","pmids":["41496210"],"is_preprint":false},{"year":2025,"finding":"USP13 interacts with and stabilizes SOCS1 by mediating K63-linked deubiquitination of SOCS1, thereby restraining excessive JAK-STAT pathway activation. USP13 knockout promotes αPD-1 resistance in CRC tumors and reduces CD8+ T-cell infiltration.","method":"Co-IP, K63-specific ubiquitination assay, USP13 KO syngeneic mouse model, flow cytometry for CD8+ T cells, JAK-STAT pathway readouts","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + K63-specific deubiquitination + KO mouse model + immune phenotyping, single lab","pmids":["42000926"],"is_preprint":false},{"year":2025,"finding":"USP13 interacts with and deubiquitinates PARP1, stabilizing PARP1 via the ubiquitin-proteasome pathway and promoting PARP1-mediated DNA damage repair in multiple myeloma cells.","method":"Mass spectrometry, Co-IP, in vitro ubiquitination assay, USP13 KD/OE, PARP1 stability assay, MM xenograft and patient-derived tumor xenograft models","journal":"Basic & clinical pharmacology & toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS + in vitro ubiquitination + in vivo models, single lab","pmids":["40151951"],"is_preprint":false},{"year":2025,"finding":"TDP-43 regulates USP13 RNA splicing; TDP-43 knockdown induces aberrant splicing of USP13 and blocks USP13 rhythmic expression, enhancing BMAL1 ubiquitination and disrupting circadian clock gene expression.","method":"TDP-43 knockdown in vivo and in vitro, RNA splicing analysis of USP13, BMAL1 ubiquitination assay, circadian wheel behavior tests","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — splicing assay + ubiquitination assay + behavioral phenotype, single lab linking TDP-43 to USP13 splicing","pmids":["40202498"],"is_preprint":false},{"year":2025,"finding":"USP13 regulates MDM2 protein by targeting its K63-linked polyubiquitination. Overexpression of USP13 reduces MDM2 levels (degradation prevented by MG132) and promotes cell senescence; knockdown increases MDM2 levels. This places USP13 in a lung aging/senescence pathway.","method":"USP13 KO mice, KD/OE in human cell lines, MDM2 stability assay with MG132, K63-specific ubiquitination assay, β-galactosidase senescence assay","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice + K63 ubiquitination assay + MG132 rescue + senescence assay, single lab; note: USP13 reduces MDM2 stability (a non-canonical DUB role), single lab","pmids":["37634814"],"is_preprint":false},{"year":2025,"finding":"USP13 interacts with GRP78 and removes K63-linked ubiquitin at K327 of GRP78, attenuating ER stress-induced apoptosis and maintaining intestinal barrier integrity. Intestinal epithelial-specific USP13 KO exacerbates DSS-induced colitis.","method":"Co-IP, site-specific K63 deubiquitination assay at K327, intestinal epithelial Usp13 KO mice, AAV9 rescue, DSS colitis model, apoptosis/ER stress markers","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + site-specific ubiquitination assay + tissue-specific KO + AAV rescue, single lab","pmids":["40679368"],"is_preprint":false},{"year":2026,"finding":"USP13 interacts with KDM3A histone demethylase and specifically removes K63-linked ubiquitin chains from KDM3A; this indirectly promotes K48-linked polyubiquitination-dependent proteasomal degradation of KDM3A in the cytoplasm, inhibiting bladder cancer metastasis.","method":"Co-IP, K63/K48-specific ubiquitination assay, USP13 KD, bladder-injected liver metastasis xenograft model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + linkage-specific ubiquitination assay + in vivo metastasis model, single lab; note: PMID 40253486 was retracted and resubmitted as PMID 41872693 with corrected cell lines","pmids":["41872693"],"is_preprint":false},{"year":2025,"finding":"USP13 stabilizes CMAS (cytidine monophosphate N-acetylneuraminic acid synthetase) by specifically cleaving K48-linked polyubiquitin chains from CMAS, enhancing melanogenic capacity. The transcription factor FOXO4 represses USP13 expression through direct promoter interaction, establishing a FOXO4-USP13-CMAS regulatory axis in melanogenesis.","method":"Proteome-ubiquitinome analysis of USP13-overexpressing melanocytes, Co-IP, K48-specific deubiquitination assay, FOXO4 luciferase reporter + EMSA","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics + Co-IP + K48 deubiquitination + EMSA for transcriptional regulation, single lab","pmids":["40876694"],"is_preprint":false},{"year":2026,"finding":"USP13 knockdown reduces insoluble TDP-43 levels and reduces cell death in primary rat motor neurons; knockdown also improves locomotor deficits in C. elegans ALS models, identifying USP13 as a modifier of TDP-43-induced aggregation and cytotoxicity.","method":"Inducible mutant TDP-43 HEK293 model, discovery proteomics via RAD23A KD, USP13 KD in HEK293 and primary rat neurons, TDP-43 solubility assay, C. elegans locomotor assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-guided discovery + KD in multiple models including primary neurons + in vivo C. elegans, single lab","pmids":["41371952"],"is_preprint":false},{"year":1998,"finding":"ISOT-3 (USP13) was identified as a novel isopeptidase T gene on human chromosome 3q26.2–q26.3, showing 54.8% amino acid identity to ISOT-1 (USP5). The exonic organization is highly conserved with ISOT-1, with USP13 having significantly larger introns (gene ≥90 kb vs 15 kb for ISOT-1), suggesting common ancestry but potentially different substrate specificities.","method":"Genomic sequencing, Northern blot analysis of tissue expression, comparative genomic organization","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 4 / Weak — genomic characterization only, no functional mechanistic assay","pmids":["9841226"],"is_preprint":false}],"current_model":"USP13 is a deubiquitinase (DUB) that removes ubiquitin chains from a broad and growing set of substrates—including PTEN, Beclin1, VPS34/PIK3C3, STING, RAP80, MCL1/Mcl-1, MITF, c-Myc, Cyclin D1, Snail, Twist1, β-catenin, ACLY, OGDH, STAT1, NLRP3, SMAD3, TopBP1, cohesin, Aurora B, ATG5, ATG7, METTL3, p62/SQSTM1, NFE2L2/NRF2, SARM1, FASN, PARP1, and others—to regulate their protein stability, localization, and activity; it predominantly removes K48-linked chains to prevent proteasomal degradation (stabilizing substrates), but can also act on K63-linked chains (sometimes non-catalytically, as with Siah2 and NLRP3) or promote autophagic degradation (STING in cardiomyocytes); upstream, USP13 activity and stability are regulated by ATM-mediated phosphorylation (at the DSB), CK2-mediated phosphorylation at Thr122, JNK-dependent proteasomal degradation in response to LPS, and TDP-43-dependent splicing, placing USP13 at the intersection of autophagy initiation, DNA damage response, innate immunity, metabolic reprogramming, and multiple cancer signaling pathways."},"narrative":{"mechanistic_narrative":"USP13 is a deubiquitinase (DUB) that controls the abundance, localization, and activity of a broad array of substrates by editing ubiquitin chains, predominantly removing K48-linked chains to oppose proteasomal degradation and stabilize its targets [PMID:24270891, PMID:37311811]. Mechanistically, USP13 has weak intrinsic isopeptidase activity and, unlike its paralog USP5, cannot be activated by free ubiquitin because its ZnF domain fails to bind free ubiquitin; its tandem UBA domains instead confer preferential binding to K63-linked diubiquitin [PMID:22216260]. This domain architecture underlies a recurring duality: USP13 acts catalytically to deubiquitinate and stabilize many substrates, but also acts non-catalytically through its ubiquitin-binding domains, as in its regulation of the E3 ligase Siah2 and its competition with the E3 ligase TRIM31 to protect NLRP3 from ubiquitination [PMID:21659512, PMID:41004574]. Through these activities USP13 sits at the intersection of several major cellular programs. In autophagy it deubiquitinates Beclin1 and, in a NEDD4-1-scaffolded complex, removes K48 chains from VPS34/PIK3C3 to promote autophagy initiation, and stabilizes ATG5 and the selective-autophagy receptor p62/SQSTM1 [PMID:21962518, PMID:32101753, PMID:37776917, PMID:36528756, PMID:39216303]. In the DNA damage response it is phosphorylated by ATM, localizes to double-strand breaks, and deubiquitinates RAP80 to support BRCA1 focus formation, while also stabilizing TopBP1 to enable ATR activation under replication stress [PMID:28569838, PMID:33592542]. In innate immunity and inflammation it deconjugates ubiquitin from STING to restrain TBK1 recruitment and antiviral signaling, and regulates NLRP3 inflammasome activity in both K48- and K63-dependent and non-catalytic modes [PMID:28534493, PMID:41004574, PMID:41206387]. Across cancers USP13 stabilizes oncogenic and metabolic regulators including PTEN, c-Myc, MCL1, cyclin D1, the metabolic enzymes ACLY and OGDH, and fatty acid synthase, thereby influencing proliferation, metabolic reprogramming, and EMT [PMID:24270891, PMID:27923907, PMID:27892457, PMID:29335437, PMID:37311811, PMID:35898882]. USP13 activity and stability are themselves regulated by upstream phosphorylation (ATM, CK2 at Thr122, Aurora B at Ser114), by JNK-dependent proteasomal degradation following LPS, and by TDP-43-dependent splicing [PMID:28569838, PMID:32772043, PMID:36612196, PMID:33169399, PMID:40202498].","teleology":[{"year":1998,"claim":"Established USP13 as a gene encoding a putative isopeptidase paralogous to USP5, raising the question of whether shared architecture implied shared or divergent substrate specificity.","evidence":"Genomic sequencing and comparative organization on chromosome 3q26","pmids":["9841226"],"confidence":"Low","gaps":["No functional or catalytic assay","Substrate specificity unaddressed"]},{"year":2011,"claim":"Defined the biochemical basis of USP13's catalytic behavior, answering why a USP5-like enzyme has weak activity and distinct chain preference.","evidence":"In vitro DUB assays on K48/K63 polyubiquitin, NMR of the ZnF domain, and domain-swap mutagenesis","pmids":["22216260"],"confidence":"High","gaps":["Does not explain how individual physiological substrates are selected","In-cell relevance of K63 preference for specific targets unresolved"]},{"year":2011,"claim":"Revealed that USP13 can act through its ubiquitin-binding domains rather than catalysis, establishing a non-catalytic mode that protects an E3 ligase (Siah2) from autodegradation.","evidence":"Catalytic vs. ubiquitin-binding domain mutants in stability assays","pmids":["21659512"],"confidence":"High","gaps":["Generality of the non-catalytic mode across substrates not yet known","Structural detail of UBA-substrate engagement unresolved"]},{"year":2011,"claim":"Connected USP13 to autophagy and melanoma growth, identifying Beclin1/Vps34 and MITF as stabilized substrates and linking USP13 to tumor maintenance.","evidence":"Spautin-1 inhibitor, shRNA DUB screen, protein stability assays, and xenografts","pmids":["21962518","21811243"],"confidence":"High","gaps":["Direct enzymatic deubiquitination of Beclin1 by USP13 not fully separated from USP10","Chain linkage on MITF not defined"]},{"year":2013,"claim":"Identified PTEN as a USP13 substrate, establishing USP13 as a tumor-suppressive regulator of PI3K/AKT signaling and glycolysis.","evidence":"DUB screen, Co-IP, in vitro deubiquitination, knockdown/overexpression, and xenografts","pmids":["24270891"],"confidence":"High","gaps":["Ubiquitin chain linkage on PTEN not specified","Counteracting E3 ligase not identified"]},{"year":2014,"claim":"Placed USP13 in ER-associated degradation, showing it maintains the Bag6 chaperone complex by deubiquitinating Ubl4A downstream of gp78.","evidence":"Co-IP, in vitro ubiquitination/deubiquitination, and ERAD substrate assays","pmids":["24424410"],"confidence":"High","gaps":["Quantitative contribution to global ERAD flux unresolved","Regulation of the gp78-USP13 association unknown"]},{"year":2016,"claim":"Extended USP13 to oncogenic stabilization and metabolic reprogramming by identifying c-Myc, ACLY, and OGDH as substrates governing stem-cell self-renewal and central carbon metabolism.","evidence":"Co-IP, ubiquitination/deubiquitination assays, T58A-Myc rescue, metabolic readouts, and in vivo models","pmids":["27923907","27892457"],"confidence":"High","gaps":["Whether metabolic enzyme stabilization is a primary or secondary effect of altered signaling unresolved"]},{"year":2017,"claim":"Defined USP13 roles in the DNA damage response and innate immunity, showing ATM phosphorylation directs it to DSBs to deubiquitinate RAP80, while it deconjugates STING to dampen antiviral signaling.","evidence":"Phosphorylation and DSB-localization assays, deubiquitination assays, and USP13 KO mice/viral challenge","pmids":["28569838","28534493"],"confidence":"High","gaps":["ATM phosphosite on USP13 not mapped","Chain linkage removed from STING in the antiviral context not defined"]},{"year":2018,"claim":"Established USP13 as a regulator of apoptotic threshold and replication-stress signaling by stabilizing MCL1 and supporting cohesin/mitotic dynamics, with therapeutic relevance to BH3 mimetics.","evidence":"siRNA screen, Co-IP, deubiquitination, CRISPR KO, BH3 mimetic sensitivity, and affinity purification/MS","pmids":["29335437","33334891"],"confidence":"High","gaps":["Paradoxical requirement for both deubiquitination and ubiquitination of cohesin mechanistically unresolved","Direct vs. indirect MCL1 chain editing not fully separated"]},{"year":2020,"claim":"Resolved how USP13 promotes autophagy initiation, showing NEDD4-1 auto-ubiquitination scaffolds USP13 to remove K48 chains from VPS34 at K419.","evidence":"Co-IP, linkage- and site-specific deubiquitination, and KO functional autophagy assays","pmids":["32101753"],"confidence":"High","gaps":["Signals controlling NEDD4-1 auto-ubiquitination upstream unresolved"]},{"year":2020,"claim":"Showed USP13 protein levels are dynamically controlled by phosphorylation (CK2/Aurora B) and LPS-induced JNK-dependent proteasomal degradation, framing USP13 as a regulated, not constitutive, node.","evidence":"Kinase and phospho-mutant assays, cycloheximide chase, inhibitor studies, and catalytic-mutant controls","pmids":["32772043","33169399","36612196"],"confidence":"Medium","gaps":["Cross-talk among the multiple phospho-inputs unresolved","JNK-dependent degradation E3 ligase not identified"]},{"year":2021,"claim":"Broadened the substrate landscape to EMT, cell cycle, and replication-stress factors (Snail, cyclin D1 precursors, TopBP1, mutant EGFR), including peptidase-independent stabilization of mutant EGFR.","evidence":"Co-IP, deubiquitination assays, MG132 rescue, Cbl epistasis, and migration/invasion assays","pmids":["34872023","33592542","33210294"],"confidence":"Medium","gaps":["Determinants of mutant- vs. wild-type EGFR selectivity unresolved","Catalytic vs. non-catalytic contribution varies by substrate and is incompletely mapped"]},{"year":2023,"claim":"Demonstrated linkage-resolved substrate editing, with K48-specific stabilization of cyclin D1, METTL3, and Twist1 and K63-specific editing of beta-catenin, tying USP13 to defined oncogenic transcriptional and epitranscriptomic programs.","evidence":"K48/K63-specific deubiquitination assays, site-directed mutagenesis, m6A profiling, and in vivo metastasis/growth models","pmids":["37311811","37151889","36732432","38043062"],"confidence":"Medium","gaps":["How a single DUB switches between K48 and K63 specificity on different substrates unresolved"]},{"year":2023,"claim":"Connected USP13 to redox and selective-autophagy regulation via p62/SQSTM1, Beclin1, and the NRF2/KEAP1 axis, positioning it as a determinant of ferroptosis sensitivity and antioxidant gene expression.","evidence":"Site-specific (p62 K7) mutagenesis, autophagy flux assays, KEAP1/NRF2 readouts, and aged KO mouse fibrosis models","pmids":["37776917","36150040"],"confidence":"Medium","gaps":["Tissue-specific balance between autophagy promotion and degradation outcomes unresolved"]},{"year":2025,"claim":"Established context-dependent, often non-catalytic control of inflammasome and immune signaling, with USP13 either stabilizing NLRP3 (by competing with TRIM31) or restraining it via K63 editing at K557, and restraining JAK-STAT via SOCS1.","evidence":"Site-specific K192/K496/K557 ubiquitination assays, DUB-dead mutants, KO macrophages/cardiomyocytes in vivo, and immune phenotyping","pmids":["41004574","41206387","42000926"],"confidence":"High","gaps":["Cell-type determinants that switch USP13 between activating and inhibiting NLRP3 unresolved"]},{"year":2025,"claim":"Defined cardioprotective and tissue-homeostasis roles in vivo through deubiquitination of STAT1, ALDOA, GRP78, and SMAD3, and a non-canonical STING route to autolysosomal degradation, supported by tissue-specific KO and AAV9 rescue.","evidence":"Interactome/MS, site-specific deubiquitination, cardiomyocyte/intestinal/HSC-specific KO, and AAV9 therapeutic overexpression in disease models","pmids":["40593642","41496210","40679368","40719972","40487656"],"confidence":"Medium","gaps":["Whether STING is stabilized or routed for degradation is context-dependent and mechanistically unreconciled across tissues"]},{"year":2025,"claim":"Linked USP13 expression and splicing to upstream transcriptional and RNA-regulatory control (HIF-1alpha, YY1, RREB1/KRAS, FOXO4, TDP-43), and to TDP-43 proteinopathy as a disease modifier.","evidence":"ChIP/promoter/EMSA assays, m6A/IGF2BP2 stabilization, and TDP-43 knockdown splicing and ALS-model phenotyping","pmids":["41330897","40319251","38043062","40876694","40202498","41371952"],"confidence":"Medium","gaps":["Direct causal role of USP13 splicing changes in human neurodegeneration unresolved"]},{"year":null,"claim":"It remains unresolved what governs USP13's choice between catalytic and ubiquitin-binding-only modes and between K48 vs K63 chain editing on a per-substrate basis, and how a single DUB produces opposing outcomes (stabilization vs. degradation, pro- vs. anti-inflammatory) in different tissues.","evidence":"No single study in the corpus reconciles the divergent mechanisms across substrates and contexts","pmids":[],"confidence":"Medium","gaps":["No unifying structural model of substrate/linkage selection","Tissue-specific cofactors directing opposing outcomes not identified","No catalytic-domain co-structure with a physiological substrate"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,6,8,12,25,39,42,44]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3,4,25,42]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,39,38]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,13,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11,15,52]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[9,13]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,12,26,33,34]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[9,17,48]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,16,39,44,47]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,12,43]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[13,14,25]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,37,45,46]}],"complexes":["NEDD4-1–USP13 complex","Bag6 chaperone complex (gp78-associated)"],"partners":["PTEN","MCL1","STING","NLRP3","BECLIN1","VPS34","ACLY","RAP80"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92995","full_name":"Ubiquitin carboxyl-terminal hydrolase 13","aliases":["Deubiquitinating enzyme 13","Isopeptidase T-3","ISOT-3","Ubiquitin thioesterase 13","Ubiquitin-specific-processing protease 13"],"length_aa":863,"mass_kda":97.3,"function":"Deubiquitinase that mediates deubiquitination of target proteins such as BECN1, MITF, SKP2 and USP10 and is involved in various processes such as autophagy, endoplasmic reticulum-associated degradation (ERAD), cell cycle progression or DNA damage response (PubMed:21571647, PubMed:32772043, PubMed:33592542). Component of a regulatory loop that controls autophagy and p53/TP53 levels: mediates deubiquitination of BECN1, a key regulator of autophagy, leading to stabilize the PIK3C3/VPS34-containing complexes. Alternatively, forms with NEDD4 a deubiquitination complex, which subsequently stabilizes VPS34 to promote autophagy (PubMed:32101753). Also deubiquitinates USP10, an essential regulator of p53/TP53 stability. In turn, PIK3C3/VPS34-containing complexes regulate USP13 stability, suggesting the existence of a regulatory system by which PIK3C3/VPS34-containing complexes regulate p53/TP53 protein levels via USP10 and USP13. Recruited by nuclear UFD1 and mediates deubiquitination of SKP2, thereby regulating endoplasmic reticulum-associated degradation (ERAD). Also regulates ERAD through the deubiquitination of UBL4A a component of the BAG6/BAT3 complex. Mediates stabilization of SIAH2 independently of deubiquitinase activity: binds ubiquitinated SIAH2 and acts by impairing SIAH2 autoubiquitination. Regulates the cell cycle progression by stabilizing cell cycle proteins such as SKP2 and AURKB (PubMed:32772043). In addition, plays an important role in maintaining genomic stability and in DNA replication checkpoint activation via regulation of RAP80 and TOPBP1 (PubMed:33592542). Deubiquitinates the multifunctional protein HMGB1 and subsequently drives its nucleocytoplasmic localization and its secretion (PubMed:36585612). Positively regulates type I and type II interferon signalings by deubiquitinating STAT1 but negatively regulates antiviral response by deubiquitinating STING1 (PubMed:23940278, PubMed:28534493)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q92995/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/USP13","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SMC1A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/USP13","total_profiled":1310},"omim":[{"mim_id":"609818","title":"UBIQUITIN-SPECIFIC PROTEIN 10; USP10","url":"https://www.omim.org/entry/609818"},{"mim_id":"604378","title":"BECLIN 1; BECN1","url":"https://www.omim.org/entry/604378"},{"mim_id":"603591","title":"UBIQUITIN-SPECIFIC PROTEASE 13; USP13","url":"https://www.omim.org/entry/603591"},{"mim_id":"191170","title":"TUMOR PROTEIN p53; TP53","url":"https://www.omim.org/entry/191170"},{"mim_id":"180468","title":"RIBOSOMAL PROTEIN L35A; RPL35A","url":"https://www.omim.org/entry/180468"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":39.8},{"tissue":"skeletal 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research","url":"https://pubmed.ncbi.nlm.nih.gov/40814378","citation_count":1,"is_preprint":false},{"pmid":"40208227","id":"PMC_40208227","title":"USP13 Facilitates the Proliferation of Hepatocellular Carcinoma Cells by Reducing K48/63-Linked Polyubiquitination and Degradation of PRPF6.","date":"2025","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40208227","citation_count":1,"is_preprint":false},{"pmid":"41293996","id":"PMC_41293996","title":"ASNS Regulates H2O2-Induced Senescence, Oxidative Stress, and Glucose Metabolism in ARPE-19 Cells by Modulating USP13 Expression.","date":"2025","source":"BioFactors (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41293996","citation_count":1,"is_preprint":false},{"pmid":"40253486","id":"PMC_40253486","title":"Non-classic deubiquitinase USP13 inhibits bladder cancer metastasis through destabilizing cytoplasmic 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cancer.","date":"2026","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/42000926","citation_count":0,"is_preprint":false},{"pmid":"41213070","id":"PMC_41213070","title":"Microvascular Endothelial Cell-Derived Exosomes Decrease Osteoclastogenesis by Restraining Osteoclast Ferroptosis through the USP13/NRF2/GPX4 Pathway.","date":"2025","source":"Critical reviews in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41213070","citation_count":0,"is_preprint":false},{"pmid":"42056074","id":"PMC_42056074","title":"USP13 promotes enzalutamide resistance by catalyzing depolyubiquitination of PCMT1 in prostate cancer.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/42056074","citation_count":0,"is_preprint":false},{"pmid":"41237839","id":"PMC_41237839","title":"METTL3-mediated m6A modification of circCDYL promotes gastric cancer progression by acting as miR-378a-5p sponge to regulate USP13 expression.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41237839","citation_count":0,"is_preprint":false},{"pmid":"41223669","id":"PMC_41223669","title":"USP13 exacerbates the malignant progression of cervical cancer by inhibiting ECT2 ubiquitination and degradation.","date":"2025","source":"Reproductive biology","url":"https://pubmed.ncbi.nlm.nih.gov/41223669","citation_count":0,"is_preprint":false},{"pmid":"42195268","id":"PMC_42195268","title":"USP13 Downregulation Distinguishes Malignant from Adjacent Non-Neoplastic Prostate Tissue and Suggests Altered PTEN-Related Regulatory Pathways in a Korean Cohort.","date":"2026","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/42195268","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50545,"output_tokens":14054,"usd":0.181223,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":25673,"output_tokens":5834,"usd":0.137107,"stage2_stop_reason":"end_turn"},"total_usd":0.31833,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"USP13 deubiquitinates Beclin1, and Beclin1 in turn controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. USP13 (with USP10) targets the Beclin1 subunit of Vps34 PI3 kinase complexes; inhibition of USP13 promotes degradation of Vps34 complexes. Because USP10 mediates deubiquitination of p53, Beclin1 regulation of USP13/USP10 activity connects p53 levels to autophagy.\",\n      \"method\": \"Small-molecule inhibitor (spautin-1) targeting USP10/USP13, Co-IP, protein stability assays in cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional assays, inhibitor + genetic knockdown, multiple orthogonal methods, widely replicated\",\n      \"pmids\": [\"21962518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"USP13 deubiquitinates MITF (microphthalmia-associated transcription factor), stabilizing MITF protein levels. Knockdown of USP13 leads to loss of MITF protein without affecting mRNA, demonstrating post-translational stabilization. USP13 modulates MITF downstream target gene expression and is required for melanoma growth.\",\n      \"method\": \"shRNA library screen against DUBs, USP13 knockdown, protein stability assays, in vivo nude mouse xenograft\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA screen plus functional validation, multiple assays in single lab\",\n      \"pmids\": [\"21811243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"USP13 regulates Siah2 E3 ubiquitin ligase stability and activity via its ubiquitin-binding domains (UBA and UBP domains) rather than its catalytic isopeptidase activity. USP13 binds ubiquitinated Siah2 and prevents its autodegradation, but this effect is abolished by mutations in ubiquitin-binding sequences, not catalytic site mutations. Consequently, USP13 attenuates Siah2's ability to target its substrates (PHD3, Spry2).\",\n      \"method\": \"Overexpression, shRNA knockdown, site-directed mutagenesis of catalytic and ubiquitin-binding domains, protein stability assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis distinguishing catalytic vs. non-catalytic mechanism, multiple constructs tested in single lab\",\n      \"pmids\": [\"21659512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"USP13 exhibits weak deubiquitinating activity preferring K63-linked polyubiquitin, operating in a non-activation manner. The ZnF domain of USP13, unlike that of its paralog USP5, cannot bind free ubiquitin and therefore USP13 cannot be activated by free ubiquitin. Substitution of the USP13 ZnF domain with the USP5 ZnF domain confers catalytic activation. The tandem UBA domains preferentially bind K63-linked diubiquitin, explaining the substrate preference.\",\n      \"method\": \"Biochemical DUB assays with K48/K63 polyubiquitin substrates, NMR structural analysis of ZnF domain, domain-swap mutagenesis, cell-based CD3δ regulation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assay + NMR structure + mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22216260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"USP13 physically associates with PTEN and deubiquitinates PTEN to stabilize its protein levels. Loss of USP13 in breast cancer cells promotes AKT phosphorylation, proliferation, anchorage-independent growth, and glycolysis through downregulation of PTEN.\",\n      \"method\": \"DUB screen (30 DUBs) for PTEN physical association, Co-IP, in vitro deubiquitination assay, USP13 knockdown/overexpression, in vivo xenograft\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — screen + Co-IP + in vitro deubiquitination assay + in vivo, widely replicated across subsequent studies\",\n      \"pmids\": [\"24270891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USP13 is a gp78-associated deubiquitinase that removes ubiquitin conjugates from Ubl4A (a component of the Bag6 chaperone complex), preventing gp78-mediated polyubiquitination and irreversible proteolytic inactivation of Bag6. This maintains the functionality of the Bag6 chaperone complex in ERAD, sharpening substrate specificity for the gp78 E3 ligase.\",\n      \"method\": \"Co-IP identifying USP13 association with gp78, in vitro ubiquitination/deubiquitination assays, cell-based ERAD substrate degradation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution/in vitro assay + Co-IP + functional ERAD assay, multiple orthogonal methods in single publication\",\n      \"pmids\": [\"24424410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP13 deubiquitinates and stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination of c-Myc, thereby maintaining glioblastoma stem cell (GSC) self-renewal and tumorigenic potential. Depletion of USP13 promotes c-Myc ubiquitination and degradation. The ubiquitin-insensitive T58A-c-Myc mutant rescues the effects of USP13 disruption or FBXL14 overexpression.\",\n      \"method\": \"Co-IP, ubiquitination assays, USP13 knockdown/overexpression, T58A-c-Myc rescue experiments, in vivo tumor growth assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + ubiquitination assay + genetic epistasis via rescue mutant, multiple orthogonal methods\",\n      \"pmids\": [\"27923907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP13 specifically deubiquitinates and upregulates ATP citrate lyase (ACLY) and oxoglutarate dehydrogenase (OGDH), two key metabolic enzymes determining mitochondrial respiration, glutaminolysis, and fatty acid synthesis in ovarian cancer cells.\",\n      \"method\": \"Co-IP, deubiquitination assays, knockdown/overexpression with metabolic readouts, in vivo ovarian tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + deubiquitination assay + functional metabolic assays, multiple orthogonal methods single lab\",\n      \"pmids\": [\"27892457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP13 interacts with STING and deconjugates polyubiquitin chains from STING, preventing the recruitment of TBK1 to the STING signaling complex and thereby negatively regulating antiviral responses. USP13 knockout mice are more resistant to lethal HSV-1 infection.\",\n      \"method\": \"Co-IP identifying USP13-STING interaction, in vitro deubiquitination assay, USP13 KD/KO cells and knockout mice, IRF3/NF-κB activation assays, viral replication assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + deubiquitination assay + KO mice + mechanistic TBK1 recruitment assay, multiple orthogonal methods\",\n      \"pmids\": [\"28534493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP13 is phosphorylated by ATM kinase following DNA damage, which facilitates its localization to DNA double-strand breaks (DSBs). USP13 then deubiquitinates RAP80, promoting RAP80 recruitment and proper DNA damage response (DDR) including BRCA1 complex foci formation.\",\n      \"method\": \"Co-IP, phosphorylation assays, DSB localization by immunofluorescence, RAP80 ubiquitination assays, USP13 depletion/inhibition sensitivity assays in ovarian cancer cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation-localization-deubiquitination axis with multiple assays, single lab\",\n      \"pmids\": [\"28569838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP13 interacts with and stabilizes MCL1 via deubiquitination, regulating MCL1 turnover in lung and ovarian cancer cells. CRISPR/Cas9-mediated USP13 depletion reduces MCL1 protein abundance and increases sensitivity to BH3 mimetic inhibitors.\",\n      \"method\": \"Unbiased siRNA screen, Co-IP, deubiquitination assay, CRISPR/Cas9 KO, in vivo xenograft, BH3 mimetic sensitivity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA screen + Co-IP + deubiquitination assay + CRISPR KO, independently replicated (also confirmed in cervical cancer PMID 33627786)\",\n      \"pmids\": [\"29335437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP5 and USP13 are recruited to heat-induced stress granules via their deubiquitylating activities. Depletion of USP13 elevates ubiquitin chain levels in stress granules, accelerates their assembly, and markedly impairs their disassembly after heat stress removal. USP13 regulates stress granule dynamics by deubiquitylating protein-conjugated ubiquitin chains.\",\n      \"method\": \"Immunofluorescence recruitment assay, siRNA knockdown, ubiquitin chain level measurements, stress granule assembly/disassembly kinetics\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization to stress granules with functional depletion phenotype, single lab\",\n      \"pmids\": [\"29567855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The E3 ubiquitin ligase NEDD4-1 undergoes K29-linked auto-ubiquitination at K1279, which serves as a scaffold to recruit USP13. The resulting NEDD4-1–USP13 complex deubiquitinates VPS34/PIK3C3 by removing K48-linked poly-ubiquitin chains at K419, stabilizing VPS34 and promoting autophagy initiation.\",\n      \"method\": \"Co-IP, deubiquitination assay, ubiquitin linkage-specific analysis, NEDD4-1 and USP13 KO cell lines, autophagosome formation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro deubiquitination + Co-IP + site-specific ubiquitin mapping + KO functional assay, multiple orthogonal methods\",\n      \"pmids\": [\"32101753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP13 interacts with cohesin and its ubiquitin-binding domains (UBA1/2) are required for this interaction. The interaction occurs specifically in the soluble nuclear fraction and preferentially during DNA replication. USP13 is paradoxically required for both deubiquitination and ubiquitination of cohesin subunits, and is required for dissociation of cohesin from chromatin as cells transit through mitosis, but is dispensable for sister chromatid cohesion.\",\n      \"method\": \"Endogenous dual-affinity purification + mass spectrometry, Co-IP in multiple cell lines, domain mapping (UBA1/2 mutants), CRISPR KO, cell fractionation, mitotic chromosome spreads\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal affinity purification/MS + domain mapping + CRISPR KO + multiple cell lines, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33334891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP13 associates with Aurora B kinase and stabilizes Aurora B, especially before mitotic entry. Aurora B-mediated phosphorylation of USP13 at Serine 114 promotes their association. USP13 instigates Aurora B deubiquitination and/or protects it from degradation in a manner that may be partially non-catalytic. Modulation of USP13 levels/activity affects unperturbed cell-cycle progression.\",\n      \"method\": \"Co-IP, phosphorylation assays, USP13 gain/loss-of-function, protein stability assays, cell cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + phosphorylation mapping + functional cell-cycle assays, non-catalytic mechanism partially inferred, single lab\",\n      \"pmids\": [\"32772043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP13 deubiquitinates and stabilizes Smad4 in lung fibroblast cells. USP13 and Smad4 co-localize in the cytoplasm and co-translocate to the nucleus in response to TGF-β1. USP13 deficiency in mice reduces extracellular matrix (ECM) protein levels, demonstrating a role in ECM expression regulation through Smad4 stabilization.\",\n      \"method\": \"Co-IP, pulse-chase protein stability assay, USP13 KO mice, overexpression/knockdown, immunofluorescence co-localization\",\n      \"journal\": \"Translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + stability assay + KO mice, single lab with multiple methods\",\n      \"pmids\": [\"32434004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP13 deubiquitinates and stabilizes IL-1R8/Sigirr, an anti-inflammatory receptor. USP13 levels directly correlate with IL-1R8/Sigirr; knockdown increases IL-1R8/Sigirr poly-ubiquitination and degradation, enhancing TLR4 signaling and cytokine release. USP13-deficient mice are highly susceptible to LPS- and Pseudomonas-induced lung injury, and IL-1R8/Sigirr overexpression rescues the inflammatory phenotype.\",\n      \"method\": \"Receptor ligation chase model, Co-IP, poly-ubiquitination assay, USP13 KO mice, acute lung injury model, IL-1R8/Sigirr overexpression rescue\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice + Co-IP + ubiquitination assay + genetic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"31204278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP13 binds to TopBP1 and stabilizes it via deubiquitination, facilitating ATR activation in response to replication stress. Depletion of USP13 impedes ATR activation and hypersensitizes cells to replication stress-inducing agents.\",\n      \"method\": \"Co-IP, deubiquitination assay, USP13 knockdown, ATR activation assays, replication stress sensitivity assays\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + deubiquitination assay + functional ATR assay, single lab\",\n      \"pmids\": [\"33592542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP13 interacts with Snail transcription factor and deubiquitinates it, stabilizing Snail protein and promoting EMT and metastasis in gastric cancer. USP13 knockdown promotes Snail degradation blockable by proteasome inhibitor MG132; Snail knockdown blocks USP13-induced migration.\",\n      \"method\": \"Co-IP, deubiquitination assay, proteasome inhibitor rescue, knockdown/overexpression, migration/invasion assays\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + deubiquitination + MG132 rescue + epistasis, single lab\",\n      \"pmids\": [\"34872023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP13 deubiquitinates and stabilizes Mcl-1 in cervical cancer cells. USP13 depletion reduces Mcl-1 expression, inhibits cell proliferation, and increases sensitivity to BH3 mimetic ABT-263.\",\n      \"method\": \"Co-IP, deubiquitination assay, USP13 knockdown, Mcl-1 stability assays, BH3 mimetic sensitivity\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + deubiquitination assay + functional phenotype, single lab\",\n      \"pmids\": [\"33627786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP13 deubiquitinates IRAK4 in macrophages. Myeloid-specific USP13 deficiency increases LPS-induced pro-inflammatory responses and worsens septic symptoms in mice, which can be rescued by IRAK4 inhibitor co-administration.\",\n      \"method\": \"USP13 myeloid-specific KO mice (USP13MKO), Co-IP/deubiquitination assay, IRAK4 inhibitor rescue, BMDM inflammatory assays, sepsis mouse model\",\n      \"journal\": \"Microbes and infection\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice + deubiquitination assay + pharmacological rescue, single lab\",\n      \"pmids\": [\"34298177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP13 binds ZHX2 (Zinc Fingers And Homeoboxes 2) and promotes ZHX2 deubiquitination and protein stability in an enzymatically dependent manner. USP13 depletion leads to ZHX2 downregulation and decreased ccRCC cell proliferation.\",\n      \"method\": \"DUB cDNA library binding screen, Co-IP, deubiquitination assay, USP13 depletion, 2D/3D growth assays, in vivo tumor growth\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cDNA library screen + Co-IP + deubiquitination assay + in vivo, single lab\",\n      \"pmids\": [\"36037364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"N6-methyladenosine (m6A) modification by METTL3 (read by IGF2BP2) stabilizes USP13 mRNA. USP13 protein interacts with ATG5 and stabilizes ATG5 via deubiquitination; PAK1 kinase-mediated phosphorylation of ATG5 enhances its interaction with USP13. This USP13-ATG5 axis enhances autophagy and imatinib resistance in GIST cells.\",\n      \"method\": \"Co-IP, deubiquitination assay, PAK1 phosphorylation assay, m6A-seq, USP13 inhibitor (spautin-1) + 3-MA treatment in xenograft models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + deubiquitination + phosphorylation assay + in vivo, single lab with multiple methods\",\n      \"pmids\": [\"36528756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Casein kinase 2 (CK2) directly interacts with USP13 and phosphorylates it at Thr122, promoting the stability of USP13 protein. Thr122 phosphorylation is important for ovarian cancer cell proliferation.\",\n      \"method\": \"Co-IP, kinase assay, phospho-specific detection, phosphorylation-deficient and phosphomimetic mutants, cell proliferation assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + kinase assay + phosphomutant functional analysis, single lab\",\n      \"pmids\": [\"36612196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP13 modulates the stability of the APC/C adaptor CDH1. USP13 binds CDH1 and its overexpression increases CDH1 levels while depletion decreases them, establishing a USP13-CDH1-Aurora B regulatory axis for cell cycle progression.\",\n      \"method\": \"Co-IP, Western blot after USP13 overexpression/siRNA/shRNA, cell cycle analysis\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP + protein level change, no direct deubiquitination assay for CDH1, single lab single method\",\n      \"pmids\": [\"35397714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP13 deubiquitinates and stabilizes cyclin D1 by physically binding to its N-terminal domain and removing K48-linked (but not K63-linked) polyubiquitin chains, promoting G1/S cell cycle progression and proliferation in gastric cancer cells.\",\n      \"method\": \"Co-IP, deubiquitination assay with K48/K63 ubiquitin mutants, USP13 KO/overexpression, cell cycle analysis, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro deubiquitination assay + domain binding + K-specific ubiquitin mutants + in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"37311811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP13 directly binds p62/SQSTM1 and removes ubiquitin at Lys7 (K7) of the PB1 domain. This deubiquitination enhances p62 protein stability and facilitates p62 oligomerization, resulting in increased selective autophagy and degradation of Keap1, thereby promoting Nrf2 activation and antioxidant gene expression.\",\n      \"method\": \"Co-IP, site-directed mutagenesis (K7), ubiquitination assay, autophagy flux assays, Keap1/Nrf2 pathway readouts\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + site-specific mutagenesis + functional pathway assay, single lab\",\n      \"pmids\": [\"37776917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP13 interacts with and deubiquitinates METTL3 at K488 by removing K48-linked ubiquitin chains, stabilizing METTL3 and increasing global m6A abundance in osteosarcoma cells, which promotes ATG5 mRNA stability and autophagy-associated malignancy.\",\n      \"method\": \"Co-IP, deubiquitination assay with K48 ubiquitin mutants, RNA-seq, m6A-IP sequencing, USP13 inhibitor in xenograft\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + deubiquitination + multiomics + in vivo, single lab\",\n      \"pmids\": [\"37151889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP13 interacts with Twist1 and specifically cleaves K48-linked polyubiquitin chains from Twist1 induced by FBXL14, stabilizing Twist1 and promoting breast cancer cell migration and invasion. Twist1 in turn inhibits USP13 transcriptional activity, forming a negative feedback loop.\",\n      \"method\": \"Co-IP, GST pulldown, deubiquitination assay with K48-specific ubiquitin, USP13 KD/OE, migration/invasion and in vivo lung metastasis assays, luciferase reporter for USP13 promoter\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pulldown + K48-specific deubiquitination assay + in vivo, single lab\",\n      \"pmids\": [\"36732432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KRAS drives expression of USP13 through the transcription factor RREB1. Elevated USP13 removes K63-linked polyubiquitination of β-catenin at lysine 508, enhancing binding of β-catenin to TCF4 and promoting KRAS-mutant NSCLC metastasis.\",\n      \"method\": \"ChIP/reporter assays for RREB1-USP13 axis, Co-IP, K63-specific deubiquitination assay, K508 site mutation, metastasis assays in vitro and in vivo\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional axis + site-specific deubiquitination + functional metastasis assays, single lab\",\n      \"pmids\": [\"38043062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP13 interacts with and deubiquitinates SARM1 (axon degeneration executor). USP13 deubiquitination of SARM1 increases the inhibitory interaction between SARM1's N-terminal ARM domain and C-terminal TIR domain, suppressing SARM1 activation and delaying injury-induced axon degeneration. Enzyme-dead USP13 fails to protect injured axons.\",\n      \"method\": \"Proximity labeling/proteomics to identify SARM1 interactome, overexpression of WT vs. enzyme-dead USP13, domain interaction assays, axon degeneration assays\",\n      \"journal\": \"Life medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics + enzymatic dead mutant + domain interaction assay + functional axon assay, single lab\",\n      \"pmids\": [\"39872893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP13 deubiquitinates Beclin 1 (distinct from the earlier finding that Beclin1 regulates USP13). In aged Usp13-deficient mice, impaired Beclin 1 deubiquitination leads to insufficient autophagic activity and increased vulnerability to bleomycin-induced lung fibrosis.\",\n      \"method\": \"USP13-deficient aged mice, Beclin 1 deubiquitination assay, Beclin 1 overexpression rescue, bleomycin fibrosis model\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice + deubiquitination assay + genetic rescue, single lab\",\n      \"pmids\": [\"36150040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP13 protein is degraded in response to LPS in Kupffer cells via the ubiquitin-proteasome system. LPS increases USP13 polyubiquitination and reduces its protein stability (not transcription). Inhibition of c-Jun N-terminal kinase (JNK) attenuates USP13 degradation, indicating JNK-dependent new protein synthesis is necessary for USP13 degradation. A catalytically inactive USP13 shows similar degradation, indicating the mechanism is activity-independent.\",\n      \"method\": \"LPS treatment, proteasome/lysosome inhibitor experiments, JNK inhibitor, cycloheximide chase, catalytic mutant USP13\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological inhibitors + catalytic mutant + stability assays, single lab\",\n      \"pmids\": [\"33169399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP13 deubiquitinates and stabilizes ATG5 in gastrointestinal stromal tumor cells (also confirmed in AML). PAK1-mediated phosphorylation of ATG5 enhances the ATG5-USP13 interaction.\",\n      \"method\": \"Co-IP, deubiquitination assay, PAK1 inhibition, USP13 knockdown, autophagy flux and tumor growth assays\",\n      \"journal\": \"Cell death and differentiation / Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + deubiquitination + phosphorylation assay, replicated in two cancer types (PMID 36528756, 39216303)\",\n      \"pmids\": [\"36528756\", \"39216303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP13 interacts with and deubiquitinates NFE2L2/NRF2, upregulating NRF2 protein levels. In KRAS-mutant lung adenocarcinoma, USP13 depletion promotes an autophagy-to-ferroptosis switch through the NRF2-SQSTM1/p62-KEAP1 axis.\",\n      \"method\": \"DUB screen (85 DUBs), Co-IP, deubiquitination assay, USP13 KD in vitro and xenograft, autophagy/ferroptosis markers\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — screen + Co-IP + deubiquitination + in vivo, single lab\",\n      \"pmids\": [\"39360581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP13 interacts with TAK1 (transforming growth factor β-activated kinase 1) and inhibits K63-linked ubiquitination and phosphorylation of TAK1, thereby dampening downstream inflammatory pathways (NF-κB) and promoting insulin signaling in the context of NAFLD.\",\n      \"method\": \"Co-IP, ubiquitination assay (K63-specific), TAK1 inhibitor rescue, USP13 overexpression/KO mice, NAFLD models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + K63-specific ubiquitination assay + KO mice + pharmacological rescue, single lab\",\n      \"pmids\": [\"39033101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP13 deubiquitinates ATG7 (autophagy-related 7) by preventing its degradation, stabilizing ATG7 protein and promoting ferroptosis in chicken granulosa cells.\",\n      \"method\": \"USP13 overexpression/knockdown, Co-IP, deubiquitination assay, ferroptosis markers (GSH, lipid peroxidation, iron)\",\n      \"journal\": \"Poultry science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP + single deubiquitination assay, non-mammalian model (chicken), single lab\",\n      \"pmids\": [\"39214053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP13 interacts with FASN (fatty acid synthase) and enhances FASN protein stability, with this USP13-FASN axis required for SCLC cancer stem cell maintenance and lipogenesis. Effect requires enzymatic activity of USP13 (inactive mutant cannot rescue).\",\n      \"method\": \"Co-IP, protein stability assay, WT vs. inactive USP13 rescue, sphere formation assay, in vivo tumor growth\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + inactive-mutant rescue + in vivo, single lab\",\n      \"pmids\": [\"35898882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP13 selectively stabilizes mutant EGFR (but not wild-type EGFR) in a peptidase-independent manner by counteracting the action of Cbl family E3 ubiquitin ligases.\",\n      \"method\": \"Unbiased high-throughput siRNA screen, USP13 KD, Cbl ligase functional assays, mutant vs. WT EGFR stability, in vitro and in vivo sensitivity assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA screen + functional Cbl epistasis + mutant specificity assay, single lab; non-catalytic mechanism supported by peptidase-independence\",\n      \"pmids\": [\"33210294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP13 stabilizes NLRP3 independently of its deubiquitinating enzyme activity by competing with E3 ligase TRIM31 to interact with NLRP3, preventing TRIM31-mediated ubiquitination of NLRP3 at K192 and K496, thereby inhibiting proteasomal degradation of NLRP3 and promoting NLRP3 inflammasome assembly and activation.\",\n      \"method\": \"Co-IP, ubiquitination assay with site-specific NLRP3 K192/K496 mutants, USP13 KO in human and mouse macrophages, DUB-dead mutant analysis, inflammasome activation readouts, peritonitis mouse model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-specific mutagenesis + DUB-dead mutant + KO in two species + in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"41004574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP13 deubiquitinates STAT1, reducing its degradation. In cardiomyocytes, USP13 promotes STAT1-targeted Nppb gene transcription and enhances mitochondrial function. Cardiomyocyte-specific Usp13 knockout aggravates pressure overload-induced cardiac hypertrophy, while AAV9-mediated USP13 overexpression has therapeutic effects.\",\n      \"method\": \"Interactome analysis identifying STAT1 as substrate, Co-IP, deubiquitination assay, cardiomyocyte-specific KO mice (TAC/Ang II models), AAV9 overexpression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interactome + Co-IP + deubiquitination assay + tissue-specific KO + therapeutic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"40593642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP13 deubiquitinates the stimulator of interferon genes (STING) and promotes its autolysosome-related degradation (rather than stabilization), alleviating cardiomyocyte inflammation in doxorubicin-induced cardiotoxicity. Cardiomyocyte-specific USP13 KO exacerbates cardiotoxicity while overexpression mitigates it.\",\n      \"method\": \"RNA-seq, Co-IP, deubiquitination assay, cardiomyocyte-specific KO mice, AAV9 overexpression, autophagy flux assays\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + deubiquitination + KO mice + AAV rescue, single lab; note: contrasts with PMID 28534493 where USP13 stabilizes STING in innate immunity; context-dependent\",\n      \"pmids\": [\"40487656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP13 deubiquitinates SMAD3 by removing K48-linked ubiquitin chains at K13 of SMAD3's MH2 domain (USP13 C345 is the catalytic cysteine involved), stabilizing SMAD3 and enhancing its transcriptional activity for profibrotic genes, thereby promoting hepatic stellate cell activation and liver fibrosis.\",\n      \"method\": \"Co-IP/MS substrate identification, domain mapping (MH2 domain), K13 site-specific ubiquitination assay, C345 catalytic mutant, HSC-specific AAV-mediated KD, CCl4 and BDL fibrosis mouse models\",\n      \"journal\": \"Hepatology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS + site-specific assay + catalytic mutant + in vivo KD, single lab\",\n      \"pmids\": [\"40719972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP13 deubiquitinates WWP1 E3 ligase by removing K29- and K48-linked polyubiquitin chains, stabilizing WWP1 via the ubiquitin-proteasome pathway. The transcription factor YY1 activates USP13 transcription and also upregulates WWP1 through USP13.\",\n      \"method\": \"Co-IP, mass spectrometry, ubiquitination assay with K29/K48-specific chains, ChIP and luciferase assay for YY1-USP13 promoter interaction, in vivo xenograft\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS + K-specific ubiquitination assay + ChIP/luciferase, single lab\",\n      \"pmids\": [\"40319251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP13 deubiquitinates NLRP3 at K557 by removing K63-linked ubiquitin chains, inhibiting NLRP3-ASC interaction and ASC polymerization, thereby inhibiting NLRP3 inflammasome activation and alleviating pyroptosis in cardiomyocytes in diabetic cardiomyopathy.\",\n      \"method\": \"Co-precipitation + LC-MS/MS substrate identification, K557 site-specific ubiquitination assay, K63-specific ubiquitin chains, cardiomyocyte-specific KO mice (type I and II diabetic), AAV9 overexpression, NLRP3-deficient rescue\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — LC-MS/MS + site-specific K63 deubiquitination + KO mice in two diabetic models + genetic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"41206387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP13 stabilizes ACLY (ATP citrate lyase) via K48-specific deubiquitination at K726, preventing proteasomal degradation. Under hypoxia, HIF-1α transcriptionally upregulates USP13 by binding its promoter, creating a hypoxia-USP13-ACLY axis that drives ferroptosis resistance and immune evasion in HCC.\",\n      \"method\": \"Co-IP, K48-specific deubiquitination assay at K726, HIF-1α ChIP/promoter assay, USP13 inhibitor (2-Met) in PDOs and xenograft, scRNA-seq, flow cytometry\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + site-specific deubiquitination + ChIP + multiple models, single lab\",\n      \"pmids\": [\"41330897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP13 interacts with ALDOA (fructose-bisphosphate aldolase A) via its USP domain and regulates K48-linked deubiquitination and stability of ALDOA at K13, preventing its proteasomal degradation and thereby restraining ferroptosis in cardiomyocytes following myocardial infarction.\",\n      \"method\": \"Co-IP, K48-specific ubiquitination assay at K13, USP13-deficient mice + cardiac-specific AAV9 overexpression, MI surgery model, ferroptosis markers\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + site-specific deubiquitination + KO mice + AAV overexpression, single lab\",\n      \"pmids\": [\"41496210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP13 interacts with and stabilizes SOCS1 by mediating K63-linked deubiquitination of SOCS1, thereby restraining excessive JAK-STAT pathway activation. USP13 knockout promotes αPD-1 resistance in CRC tumors and reduces CD8+ T-cell infiltration.\",\n      \"method\": \"Co-IP, K63-specific ubiquitination assay, USP13 KO syngeneic mouse model, flow cytometry for CD8+ T cells, JAK-STAT pathway readouts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + K63-specific deubiquitination + KO mouse model + immune phenotyping, single lab\",\n      \"pmids\": [\"42000926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP13 interacts with and deubiquitinates PARP1, stabilizing PARP1 via the ubiquitin-proteasome pathway and promoting PARP1-mediated DNA damage repair in multiple myeloma cells.\",\n      \"method\": \"Mass spectrometry, Co-IP, in vitro ubiquitination assay, USP13 KD/OE, PARP1 stability assay, MM xenograft and patient-derived tumor xenograft models\",\n      \"journal\": \"Basic & clinical pharmacology & toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS + in vitro ubiquitination + in vivo models, single lab\",\n      \"pmids\": [\"40151951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TDP-43 regulates USP13 RNA splicing; TDP-43 knockdown induces aberrant splicing of USP13 and blocks USP13 rhythmic expression, enhancing BMAL1 ubiquitination and disrupting circadian clock gene expression.\",\n      \"method\": \"TDP-43 knockdown in vivo and in vitro, RNA splicing analysis of USP13, BMAL1 ubiquitination assay, circadian wheel behavior tests\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — splicing assay + ubiquitination assay + behavioral phenotype, single lab linking TDP-43 to USP13 splicing\",\n      \"pmids\": [\"40202498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP13 regulates MDM2 protein by targeting its K63-linked polyubiquitination. Overexpression of USP13 reduces MDM2 levels (degradation prevented by MG132) and promotes cell senescence; knockdown increases MDM2 levels. This places USP13 in a lung aging/senescence pathway.\",\n      \"method\": \"USP13 KO mice, KD/OE in human cell lines, MDM2 stability assay with MG132, K63-specific ubiquitination assay, β-galactosidase senescence assay\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice + K63 ubiquitination assay + MG132 rescue + senescence assay, single lab; note: USP13 reduces MDM2 stability (a non-canonical DUB role), single lab\",\n      \"pmids\": [\"37634814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP13 interacts with GRP78 and removes K63-linked ubiquitin at K327 of GRP78, attenuating ER stress-induced apoptosis and maintaining intestinal barrier integrity. Intestinal epithelial-specific USP13 KO exacerbates DSS-induced colitis.\",\n      \"method\": \"Co-IP, site-specific K63 deubiquitination assay at K327, intestinal epithelial Usp13 KO mice, AAV9 rescue, DSS colitis model, apoptosis/ER stress markers\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + site-specific ubiquitination assay + tissue-specific KO + AAV rescue, single lab\",\n      \"pmids\": [\"40679368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP13 interacts with KDM3A histone demethylase and specifically removes K63-linked ubiquitin chains from KDM3A; this indirectly promotes K48-linked polyubiquitination-dependent proteasomal degradation of KDM3A in the cytoplasm, inhibiting bladder cancer metastasis.\",\n      \"method\": \"Co-IP, K63/K48-specific ubiquitination assay, USP13 KD, bladder-injected liver metastasis xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + linkage-specific ubiquitination assay + in vivo metastasis model, single lab; note: PMID 40253486 was retracted and resubmitted as PMID 41872693 with corrected cell lines\",\n      \"pmids\": [\"41872693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP13 stabilizes CMAS (cytidine monophosphate N-acetylneuraminic acid synthetase) by specifically cleaving K48-linked polyubiquitin chains from CMAS, enhancing melanogenic capacity. The transcription factor FOXO4 represses USP13 expression through direct promoter interaction, establishing a FOXO4-USP13-CMAS regulatory axis in melanogenesis.\",\n      \"method\": \"Proteome-ubiquitinome analysis of USP13-overexpressing melanocytes, Co-IP, K48-specific deubiquitination assay, FOXO4 luciferase reporter + EMSA\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics + Co-IP + K48 deubiquitination + EMSA for transcriptional regulation, single lab\",\n      \"pmids\": [\"40876694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP13 knockdown reduces insoluble TDP-43 levels and reduces cell death in primary rat motor neurons; knockdown also improves locomotor deficits in C. elegans ALS models, identifying USP13 as a modifier of TDP-43-induced aggregation and cytotoxicity.\",\n      \"method\": \"Inducible mutant TDP-43 HEK293 model, discovery proteomics via RAD23A KD, USP13 KD in HEK293 and primary rat neurons, TDP-43 solubility assay, C. elegans locomotor assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-guided discovery + KD in multiple models including primary neurons + in vivo C. elegans, single lab\",\n      \"pmids\": [\"41371952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"ISOT-3 (USP13) was identified as a novel isopeptidase T gene on human chromosome 3q26.2–q26.3, showing 54.8% amino acid identity to ISOT-1 (USP5). The exonic organization is highly conserved with ISOT-1, with USP13 having significantly larger introns (gene ≥90 kb vs 15 kb for ISOT-1), suggesting common ancestry but potentially different substrate specificities.\",\n      \"method\": \"Genomic sequencing, Northern blot analysis of tissue expression, comparative genomic organization\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — genomic characterization only, no functional mechanistic assay\",\n      \"pmids\": [\"9841226\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USP13 is a deubiquitinase (DUB) that removes ubiquitin chains from a broad and growing set of substrates—including PTEN, Beclin1, VPS34/PIK3C3, STING, RAP80, MCL1/Mcl-1, MITF, c-Myc, Cyclin D1, Snail, Twist1, β-catenin, ACLY, OGDH, STAT1, NLRP3, SMAD3, TopBP1, cohesin, Aurora B, ATG5, ATG7, METTL3, p62/SQSTM1, NFE2L2/NRF2, SARM1, FASN, PARP1, and others—to regulate their protein stability, localization, and activity; it predominantly removes K48-linked chains to prevent proteasomal degradation (stabilizing substrates), but can also act on K63-linked chains (sometimes non-catalytically, as with Siah2 and NLRP3) or promote autophagic degradation (STING in cardiomyocytes); upstream, USP13 activity and stability are regulated by ATM-mediated phosphorylation (at the DSB), CK2-mediated phosphorylation at Thr122, JNK-dependent proteasomal degradation in response to LPS, and TDP-43-dependent splicing, placing USP13 at the intersection of autophagy initiation, DNA damage response, innate immunity, metabolic reprogramming, and multiple cancer signaling pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"USP13 is a deubiquitinase (DUB) that controls the abundance, localization, and activity of a broad array of substrates by editing ubiquitin chains, predominantly removing K48-linked chains to oppose proteasomal degradation and stabilize its targets [#4, #25]. Mechanistically, USP13 has weak intrinsic isopeptidase activity and, unlike its paralog USP5, cannot be activated by free ubiquitin because its ZnF domain fails to bind free ubiquitin; its tandem UBA domains instead confer preferential binding to K63-linked diubiquitin [#3]. This domain architecture underlies a recurring duality: USP13 acts catalytically to deubiquitinate and stabilize many substrates, but also acts non-catalytically through its ubiquitin-binding domains, as in its regulation of the E3 ligase Siah2 and its competition with the E3 ligase TRIM31 to protect NLRP3 from ubiquitination [#2, #39]. Through these activities USP13 sits at the intersection of several major cellular programs. In autophagy it deubiquitinates Beclin1 and, in a NEDD4-1-scaffolded complex, removes K48 chains from VPS34/PIK3C3 to promote autophagy initiation, and stabilizes ATG5 and the selective-autophagy receptor p62/SQSTM1 [#0, #12, #26, #33]. In the DNA damage response it is phosphorylated by ATM, localizes to double-strand breaks, and deubiquitinates RAP80 to support BRCA1 focus formation, while also stabilizing TopBP1 to enable ATR activation under replication stress [#9, #17]. In innate immunity and inflammation it deconjugates ubiquitin from STING to restrain TBK1 recruitment and antiviral signaling, and regulates NLRP3 inflammasome activity in both K48- and K63-dependent and non-catalytic modes [#8, #39, #44]. Across cancers USP13 stabilizes oncogenic and metabolic regulators including PTEN, c-Myc, MCL1, cyclin D1, the metabolic enzymes ACLY and OGDH, and fatty acid synthase, thereby influencing proliferation, metabolic reprogramming, and EMT [#4, #6, #7, #10, #25, #37]. USP13 activity and stability are themselves regulated by upstream phosphorylation (ATM, CK2 at Thr122, Aurora B at Ser114), by JNK-dependent proteasomal degradation following LPS, and by TDP-43-dependent splicing [#9, #14, #23, #32, #49].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established USP13 as a gene encoding a putative isopeptidase paralogous to USP5, raising the question of whether shared architecture implied shared or divergent substrate specificity.\",\n      \"evidence\": \"Genomic sequencing and comparative organization on chromosome 3q26\",\n      \"pmids\": [\"9841226\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional or catalytic assay\", \"Substrate specificity unaddressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the biochemical basis of USP13's catalytic behavior, answering why a USP5-like enzyme has weak activity and distinct chain preference.\",\n      \"evidence\": \"In vitro DUB assays on K48/K63 polyubiquitin, NMR of the ZnF domain, and domain-swap mutagenesis\",\n      \"pmids\": [\"22216260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not explain how individual physiological substrates are selected\", \"In-cell relevance of K63 preference for specific targets unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed that USP13 can act through its ubiquitin-binding domains rather than catalysis, establishing a non-catalytic mode that protects an E3 ligase (Siah2) from autodegradation.\",\n      \"evidence\": \"Catalytic vs. ubiquitin-binding domain mutants in stability assays\",\n      \"pmids\": [\"21659512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the non-catalytic mode across substrates not yet known\", \"Structural detail of UBA-substrate engagement unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected USP13 to autophagy and melanoma growth, identifying Beclin1/Vps34 and MITF as stabilized substrates and linking USP13 to tumor maintenance.\",\n      \"evidence\": \"Spautin-1 inhibitor, shRNA DUB screen, protein stability assays, and xenografts\",\n      \"pmids\": [\"21962518\", \"21811243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic deubiquitination of Beclin1 by USP13 not fully separated from USP10\", \"Chain linkage on MITF not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified PTEN as a USP13 substrate, establishing USP13 as a tumor-suppressive regulator of PI3K/AKT signaling and glycolysis.\",\n      \"evidence\": \"DUB screen, Co-IP, in vitro deubiquitination, knockdown/overexpression, and xenografts\",\n      \"pmids\": [\"24270891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin chain linkage on PTEN not specified\", \"Counteracting E3 ligase not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed USP13 in ER-associated degradation, showing it maintains the Bag6 chaperone complex by deubiquitinating Ubl4A downstream of gp78.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination/deubiquitination, and ERAD substrate assays\",\n      \"pmids\": [\"24424410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution to global ERAD flux unresolved\", \"Regulation of the gp78-USP13 association unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended USP13 to oncogenic stabilization and metabolic reprogramming by identifying c-Myc, ACLY, and OGDH as substrates governing stem-cell self-renewal and central carbon metabolism.\",\n      \"evidence\": \"Co-IP, ubiquitination/deubiquitination assays, T58A-Myc rescue, metabolic readouts, and in vivo models\",\n      \"pmids\": [\"27923907\", \"27892457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether metabolic enzyme stabilization is a primary or secondary effect of altered signaling unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined USP13 roles in the DNA damage response and innate immunity, showing ATM phosphorylation directs it to DSBs to deubiquitinate RAP80, while it deconjugates STING to dampen antiviral signaling.\",\n      \"evidence\": \"Phosphorylation and DSB-localization assays, deubiquitination assays, and USP13 KO mice/viral challenge\",\n      \"pmids\": [\"28569838\", \"28534493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ATM phosphosite on USP13 not mapped\", \"Chain linkage removed from STING in the antiviral context not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established USP13 as a regulator of apoptotic threshold and replication-stress signaling by stabilizing MCL1 and supporting cohesin/mitotic dynamics, with therapeutic relevance to BH3 mimetics.\",\n      \"evidence\": \"siRNA screen, Co-IP, deubiquitination, CRISPR KO, BH3 mimetic sensitivity, and affinity purification/MS\",\n      \"pmids\": [\"29335437\", \"33334891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Paradoxical requirement for both deubiquitination and ubiquitination of cohesin mechanistically unresolved\", \"Direct vs. indirect MCL1 chain editing not fully separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved how USP13 promotes autophagy initiation, showing NEDD4-1 auto-ubiquitination scaffolds USP13 to remove K48 chains from VPS34 at K419.\",\n      \"evidence\": \"Co-IP, linkage- and site-specific deubiquitination, and KO functional autophagy assays\",\n      \"pmids\": [\"32101753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling NEDD4-1 auto-ubiquitination upstream unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed USP13 protein levels are dynamically controlled by phosphorylation (CK2/Aurora B) and LPS-induced JNK-dependent proteasomal degradation, framing USP13 as a regulated, not constitutive, node.\",\n      \"evidence\": \"Kinase and phospho-mutant assays, cycloheximide chase, inhibitor studies, and catalytic-mutant controls\",\n      \"pmids\": [\"32772043\", \"33169399\", \"36612196\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cross-talk among the multiple phospho-inputs unresolved\", \"JNK-dependent degradation E3 ligase not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Broadened the substrate landscape to EMT, cell cycle, and replication-stress factors (Snail, cyclin D1 precursors, TopBP1, mutant EGFR), including peptidase-independent stabilization of mutant EGFR.\",\n      \"evidence\": \"Co-IP, deubiquitination assays, MG132 rescue, Cbl epistasis, and migration/invasion assays\",\n      \"pmids\": [\"34872023\", \"33592542\", \"33210294\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of mutant- vs. wild-type EGFR selectivity unresolved\", \"Catalytic vs. non-catalytic contribution varies by substrate and is incompletely mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated linkage-resolved substrate editing, with K48-specific stabilization of cyclin D1, METTL3, and Twist1 and K63-specific editing of beta-catenin, tying USP13 to defined oncogenic transcriptional and epitranscriptomic programs.\",\n      \"evidence\": \"K48/K63-specific deubiquitination assays, site-directed mutagenesis, m6A profiling, and in vivo metastasis/growth models\",\n      \"pmids\": [\"37311811\", \"37151889\", \"36732432\", \"38043062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a single DUB switches between K48 and K63 specificity on different substrates unresolved\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected USP13 to redox and selective-autophagy regulation via p62/SQSTM1, Beclin1, and the NRF2/KEAP1 axis, positioning it as a determinant of ferroptosis sensitivity and antioxidant gene expression.\",\n      \"evidence\": \"Site-specific (p62 K7) mutagenesis, autophagy flux assays, KEAP1/NRF2 readouts, and aged KO mouse fibrosis models\",\n      \"pmids\": [\"37776917\", \"36150040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific balance between autophagy promotion and degradation outcomes unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established context-dependent, often non-catalytic control of inflammasome and immune signaling, with USP13 either stabilizing NLRP3 (by competing with TRIM31) or restraining it via K63 editing at K557, and restraining JAK-STAT via SOCS1.\",\n      \"evidence\": \"Site-specific K192/K496/K557 ubiquitination assays, DUB-dead mutants, KO macrophages/cardiomyocytes in vivo, and immune phenotyping\",\n      \"pmids\": [\"41004574\", \"41206387\", \"42000926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type determinants that switch USP13 between activating and inhibiting NLRP3 unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined cardioprotective and tissue-homeostasis roles in vivo through deubiquitination of STAT1, ALDOA, GRP78, and SMAD3, and a non-canonical STING route to autolysosomal degradation, supported by tissue-specific KO and AAV9 rescue.\",\n      \"evidence\": \"Interactome/MS, site-specific deubiquitination, cardiomyocyte/intestinal/HSC-specific KO, and AAV9 therapeutic overexpression in disease models\",\n      \"pmids\": [\"40593642\", \"41496210\", \"40679368\", \"40719972\", \"40487656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STING is stabilized or routed for degradation is context-dependent and mechanistically unreconciled across tissues\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked USP13 expression and splicing to upstream transcriptional and RNA-regulatory control (HIF-1alpha, YY1, RREB1/KRAS, FOXO4, TDP-43), and to TDP-43 proteinopathy as a disease modifier.\",\n      \"evidence\": \"ChIP/promoter/EMSA assays, m6A/IGF2BP2 stabilization, and TDP-43 knockdown splicing and ALS-model phenotyping\",\n      \"pmids\": [\"41330897\", \"40319251\", \"38043062\", \"40876694\", \"40202498\", \"41371952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct causal role of USP13 splicing changes in human neurodegeneration unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what governs USP13's choice between catalytic and ubiquitin-binding-only modes and between K48 vs K63 chain editing on a per-substrate basis, and how a single DUB produces opposing outcomes (stabilization vs. degradation, pro- vs. anti-inflammatory) in different tissues.\",\n      \"evidence\": \"No single study in the corpus reconciles the divergent mechanisms across substrates and contexts\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model of substrate/linkage selection\", \"Tissue-specific cofactors directing opposing outcomes not identified\", \"No catalytic-domain co-structure with a physiological substrate\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 6, 8, 12, 25, 39, 42, 44]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3, 4, 25, 42]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 39, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 13, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11, 15, 52]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [9, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 12, 26, 33, 34]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [9, 17, 48]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 16, 39, 44, 47]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 12, 43]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [13, 14, 25]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 37, 45, 46]}\n    ],\n    \"complexes\": [\n      \"NEDD4-1\\u2013USP13 complex\",\n      \"Bag6 chaperone complex (gp78-associated)\"\n    ],\n    \"partners\": [\n      \"PTEN\",\n      \"MCL1\",\n      \"STING\",\n      \"NLRP3\",\n      \"Beclin1\",\n      \"VPS34\",\n      \"ACLY\",\n      \"RAP80\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}