{"gene":"YOD1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2009,"finding":"YOD1 is a deubiquitinating enzyme of the OTU (otubain) family that associates with the p97 AAA-ATPase complex and its deubiquitinating activity is required for dislocation of misfolded proteins from the ER (ERAD). A catalytically inactive YOD1 variant acts as a dominant negative, stabilizing dislocation substrates and increasing polyubiquitinated intermediates associated with p97 in the cytosol. The dominant-negative effect depends on the UBX and Zinc finger domains flanking the catalytic OTU core.","method":"Co-immunoprecipitation, dominant-negative catalytic mutant expression, stabilization assay of ERAD substrates in mammalian cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, dominant-negative mutagenesis, multiple ERAD substrates tested; foundational study replicated by subsequent work","pmids":["19818707"],"is_preprint":false},{"year":2015,"finding":"Both p97 and YOD1 participate in two distinct retro-translocation steps in ERAD: for substrates CD4 (Vpu-induced) and MHC-Iα (US2/US11-induced), they have a retro-translocation-triggering role, whereas for spontaneous ERAD substrates (NS1, NHK-α1AT, BST-2/Tetherin), they are required for downstream deglycosylation and proteasomal degradation steps.","method":"In vivo biotinylation retro-translocation assay in mammalian cells under impaired p97 or YOD1 activity, using multiple distinct ERAD substrates","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct retro-translocation assay with multiple orthogonal substrates, single lab but rigorous mechanistic dissection","pmids":["26463207"],"is_preprint":false},{"year":2016,"finding":"Upon lysosomal damage, p97 translocates to lysosomes and cooperates with cofactors UBXD1, PLAA, and YOD1 (termed ELDR components). Together they act downstream of K63-linked ubiquitination and p62 recruitment, and selectively remove K48-linked ubiquitin conjugates from damaged lysosomes to promote autophagosome formation, driving clearance of ruptured lysosomes by autophagy.","method":"Fluorescence imaging, co-immunoprecipitation, siRNA knockdown with lysosomal damage assay, lysosome-associated ubiquitin chain-linkage analysis, MEF p97-mutant model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (imaging, Co-IP, KO/KD, linkage-specific ubiquitin analysis), genetic disease patient tissue validation","pmids":["27753622"],"is_preprint":false},{"year":2017,"finding":"YOD1 deubiquitinates ITCH (an E3 ligase targeting LATS1/2), enhancing ITCH protein stability. This leads to increased ITCH-mediated ubiquitination and degradation of LATS1/2, resulting in elevated YAP/TAZ levels and downstream Hippo pathway activation. Inducible YOD1 expression in transgenic mice causes hepatomegaly in a YAP/TAZ-dependent manner.","method":"siRNA screening, co-immunoprecipitation, ubiquitination assay, transgenic mouse model with inducible YOD1 expression, rescue experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA screen, biochemical ubiquitination assays, in vivo transgenic model with YAP/TAZ-dependent rescue, multiple orthogonal methods","pmids":["28416659"],"is_preprint":false},{"year":2017,"finding":"YOD1 interacts with the C-terminal TRAF homology domain of TRAF6 and competes with the adaptor p62/Sequestosome-1 for TRAF6 binding. YOD1 inhibits TRAF6/p62-dependent IL-1 signaling to NF-κB by a non-catalytic mechanism: it prevents TRAF6 sequestration into cytosolic p62 aggregates. Upon IL-1β stimulation, YOD1 is released from TRAF6, facilitating TRAF6 auto-ubiquitination and NEMO/IKKγ substrate ubiquitination.","method":"Co-immunoprecipitation, competition binding assay, overexpression/depletion of YOD1, NF-κB reporter assays, IL-1β stimulation experiments in human cells","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, competition assay, gain/loss-of-function with pathway readouts, multiple orthogonal methods in single lab","pmids":["28244869"],"is_preprint":false},{"year":2019,"finding":"YOD1 is recruited to mitochondria to interact with MAVS (via its UBX and Znf domains) after viral infection. YOD1 cleaves K63-linked ubiquitin chains on MAVS and abrogates formation of prion-like MAVS aggregates, thereby attenuating IRF3, p65 activation, and IFN-β production. YOD1 knockdown potentiates antiviral innate immune signaling.","method":"Co-immunoprecipitation, mitochondrial fractionation, ubiquitination assay (K63-linkage specific), siRNA knockdown, IRF3/p65 activation assays, IFN-β measurement","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct biochemical interaction and K63-deubiquitination demonstrated, domain mapping, KD with pathway readouts, two cell systems (human and murine)","pmids":["30952814"],"is_preprint":false},{"year":2012,"finding":"APCs expressing catalytically inactive YOD1 (C160S mutant) retain antigen longer and present exogenous antigens more efficiently to CD8+ T cells. Enhanced cross-presentation is TAP1-independent but sensitive to inhibitors of acidification and the proteasome, indicating YOD1 deubiquitylase activity controls antigen processing for MHC class I cross-presentation.","method":"Catalytic mutant knock-in mouse model (YOD1-C160S), in vitro and in vivo antigen cross-presentation assays, viral infection models, pharmacological inhibitor treatment","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — catalytic mutant mouse model with in vivo viral challenge, multiple antigen/infection systems, mechanistic inhibitor experiments","pmids":["23243279"],"is_preprint":false},{"year":2018,"finding":"YOD1 exhibits deubiquitinating activity with preference for K48- and K63-linked ubiquitin chains. YOD1 reduces cytotoxicity of mutant huntingtin and mutant α-synuclein through efficient degradation of these proteins; this neuroprotective activity is abolished by a catalytically inactive YOD1 mutant. YOD1 is upregulated by proteotoxic stress and localizes to Lewy bodies in Parkinson's disease patient tissue.","method":"In vitro deubiquitination assay (K48/K63 chain preference), catalytically inactive mutant rescue experiments, immunofluorescence (Lewy body localization), stress induction assays","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro DUB assay with linkage specificity, catalytic mutant functional test, patient tissue localization; single lab","pmids":["29330040"],"is_preprint":false},{"year":2020,"finding":"YOD1 binds to NEDD4 (an E3 ligase targeting LATS1) and deubiquitinates K63-linked polyubiquitin chains on NEDD4, stabilizing NEDD4 and suppressing NEDD4-induced cell proliferation in kidney cells.","method":"Co-immunoprecipitation, ubiquitination assay (K63-linkage specific), cell proliferation assay, mouse UUO model for DUB screening","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and K63-deubiquitination of NEDD4 shown biochemically, functional cell proliferation readout; single lab","pmids":["31916733"],"is_preprint":false},{"year":2021,"finding":"YOD1 is a critical deubiquitinase that maintains the stability of the PML/RARα oncoprotein in APL cells. siRNA-mediated suppression of YOD1 promotes proteasomal degradation of PML/RARα. A small-molecule YOD1 inhibitor (G5) degrades PML/RARα and eradicates APL cells in vitro and prolongs survival in APL cell-bearing mice.","method":"DUB siRNA library screen, Western blot for PML/RARα stability, pharmacological inhibitor (G5), in vivo APL mouse model, primary patient-derived APL blasts","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased siRNA screen identifies YOD1, validated with pharmacological inhibitor in vivo and in primary patient cells; mechanistic link to ubiquitination inferred but deubiquitination of PML/RARα not directly demonstrated biochemically","pmids":["35847510"],"is_preprint":false},{"year":2023,"finding":"YOD1 directly interacts with CDK1 and deubiquitinates CDK1, preventing its proteasomal degradation and upregulating CDK1 protein levels. This interaction depends on YOD1's catalytic activity. YOD1 knockdown reduces CDK1 expression and inhibits TNBC cell proliferation, migration, and cell cycle progression.","method":"Proteomic analysis, co-immunoprecipitation, proximity ligation assay, immunofluorescence, Western blot, in vitro catalytic mutant experiments, in vivo xenograft model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by Co-IP and proximity ligation, catalytic-activity dependence shown, in vivo validation; single lab","pmids":["37667382"],"is_preprint":false},{"year":2023,"finding":"YOD1 deubiquitinates p53 and stabilizes it through interaction between the N-terminus of p53 and the OTU domain of YOD1. Loss of YOD1 in AML leads to reduced p53 stability; YOD1 overexpression stabilizes p53, upregulates pro-apoptotic p53 target genes, and increases AML cell sensitivity to FLT3 inhibitors.","method":"Co-immunoprecipitation (domain mapping), ubiquitination assay, Western blot for p53 stability, reporter gene assay for miR-221/222 targeting of YOD1 3'UTR, overexpression/knockdown functional assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Co-IP with domain mapping, ubiquitination assay for p53, functional rescue; single lab","pmids":["37454155"],"is_preprint":false},{"year":2023,"finding":"YOD1 directly interacts with α-synuclein and deubiquitinates K6-, K11-, K29-, K33-, and K63-linked polyubiquitin chains on α-synuclein. YOD1 destabilizes α-synuclein protein by also upregulating NEDD4, the E3 ligase responsible for α-synuclein degradation.","method":"Co-immunoprecipitation, in vitro deubiquitination assay with linkage-specific ubiquitin chains, Western blot for protein stability","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct binding and multi-linkage deubiquitination shown biochemically; single lab, single study","pmids":["36682332"],"is_preprint":false},{"year":2023,"finding":"YOD1 inhibits HNSCC progression by deubiquitinating and stabilizing the E3 ligase TRIM33, thereby suppressing activation of the ERK/β-catenin pathway.","method":"Co-immunoprecipitation, ubiquitination assay, Western blot for TRIM33 stability, in vitro and in vivo tumor models, pathway activity readouts","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical deubiquitination of TRIM33, pathway readouts, in vivo validation; single lab","pmids":["37573347"],"is_preprint":false},{"year":2023,"finding":"YOD1 interacts with USP21 (another DUB involved in Hippo signaling) and deubiquitinates MARK (microtubule-affinity regulating kinase). YOD1 and USP21 mutually deubiquitinate each other; YOD1 regulates USP21 protein stability (but USP21 does not regulate YOD1 stability). Combined YOD1 and USP21 activity synergistically modulates Hippo signaling and cell proliferation.","method":"Co-immunoprecipitation, GST pull-down, immunocytochemistry, Western blot for protein stability, cell proliferation/colony assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and GST pull-down, mutual deubiquitination confirmed biochemically; single lab","pmids":["37743467"],"is_preprint":false},{"year":2024,"finding":"YOD1 directly binds β-catenin via its OTU domain (with histidine 262 as the active site) and removes K48-linked ubiquitin chains from β-catenin, preventing its proteasomal degradation and stabilizing β-catenin protein. This promotes Ang II-induced endothelial-mesenchymal transition. YOD1 knockout reduces EndMT in Ang II-treated mice and HUVECs.","method":"LC-MS/MS proteomics, co-immunoprecipitation, active-site mutagenesis (H262), K48 ubiquitin chain assay, YOD1 knockout mouse model, HUVEC experiments","journal":"Acta pharmacologica Sinica","confidence":"High","confidence_rationale":"Tier 2 / Moderate — LC-MS/MS substrate identification, Co-IP, active-site mutant, K48 chain deubiquitination assay, in vivo knockout validation; multiple orthogonal methods","pmids":["38641745"],"is_preprint":false},{"year":2024,"finding":"YOD1 interacts with MYH9 (Myosin heavy chain 9) and stabilizes it by removing K48-linked ubiquitin chains, thereby mediating microglial polarization signaling. YOD1 knockout improves microglial migration, phagocytosis, and inflammatory responses, and ameliorates cognitive impairment in AD model mice.","method":"LC-MS/MS combined with co-immunoprecipitation for substrate identification, K48 ubiquitin chain assay, YOD1 knockout mouse model, behavioral/cognitive assays","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LC-MS/MS + Co-IP for substrate ID, K48 chain deubiquitination, in vivo KO model; single lab","pmids":["40041897"],"is_preprint":false},{"year":2024,"finding":"YOD1 directly interacts with NLRP3 and removes K33-linked ubiquitin chains from NLRP3, inhibiting NLRP3 expression and inflammasome activation. YOD1 deficiency enhances NLRP3 inflammasome activation and disseminated intravascular coagulation in MRSA sepsis models both in vitro and in vivo.","method":"Co-immunoprecipitation, K33-linkage specific ubiquitination assay, YOD1 knockout mouse model, in vitro/in vivo MRSA infection models, NLRP3 inhibitor rescue","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction and K33-deubiquitination of NLRP3 shown, in vivo KO model; single lab","pmids":["38789414"],"is_preprint":false},{"year":2024,"finding":"YOD1 inhibits proteasomal degradation of RIPK2 by reducing K48 polyubiquitination of RIPK2, thereby increasing RIPK2 abundance and enhancing NOD2-mediated protective signaling in macrophages against DSS-induced colitis. YOD1-deficient mice are highly susceptible to DSS colitis, and this effect is derived from hematopoietic cells (shown by bone marrow transplantation).","method":"YOD1 knockout mouse model, bone marrow transplantation, co-immunoprecipitation, K48 ubiquitination assay of RIPK2, DSS colitis model, NOD2 ligand (MDP) rescue experiments","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct deubiquitination of RIPK2, genetic epistasis via KO and bone marrow transplant, in vivo rescue with NOD2 ligand; multiple orthogonal methods","pmids":["39333628"],"is_preprint":false},{"year":2025,"finding":"YOD1 deubiquitinates STAT3 by removing K48-linked ubiquitin chains at K97 of STAT3 via the C155 active site of YOD1, stabilizing STAT3 and enhancing its nuclear translocation in cardiomyocytes under Ang II stimulation. Cardiomyocyte-specific YOD1 knockout reduces Ang II- and TAC-induced cardiac hypertrophy; STAT3 inhibition reverses the antihypertrophic effect of YOD1 deficiency.","method":"Multiple proteomic analyses for substrate identification, co-immunoprecipitation, active-site and substrate lysine mutagenesis (C155, K97), K48 ubiquitin chain assay, cardiomyocyte-specific YOD1 KO mouse model, nuclear translocation assay, in vivo hypertrophy models","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic substrate ID, active-site mutagenesis, substrate lysine mapping, K48 chain deubiquitination, cardiomyocyte-specific KO in vivo with STAT3 inhibitor rescue; multiple orthogonal methods in single rigorous study","pmids":["40561034"],"is_preprint":false},{"year":2025,"finding":"YOD1 directly binds PKM2 and selectively removes K63-linked polyubiquitin chains from PKM2 at K311 via its active site H262. This deubiquitination destabilizes PKM2 tetramers, inhibits mitochondrial oxidative phosphorylation (OXPHOS), and promotes cardiac hypertrophy. PKM2 activator TEPP-46 reverses YOD1 overexpression-induced hypertrophy and OXPHOS inhibition.","method":"Quantitative proteomic screening, co-immunoprecipitation, active-site mutagenesis (H262), substrate lysine mutagenesis (K311), K63 ubiquitin chain assay, PKM2 tetramer/dimer assay, cardiomyocyte-specific YOD1 KO mouse model, OXPHOS measurement, pharmacological rescue","journal":"Acta pharmacologica Sinica","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative proteomics, active-site and substrate lysine mutagenesis, K63 chain-specific deubiquitination, functional tetramer assay, in vivo CKO mouse model with pharmacological rescue; multiple orthogonal methods","pmids":["40500343"],"is_preprint":false},{"year":2025,"finding":"YOD1 directly interacts with NCOA4 via its OTU domain and inhibits K48-linked ubiquitination at K343/K353 of NCOA4, thereby stabilizing NCOA4 and facilitating NCOA4-mediated autophagic degradation of ferritin heavy chain 1 (FTH1), promoting ferroptosis in acute lung injury.","method":"Co-immunoprecipitation, domain-mapping experiments (OTU domain), K48-linkage ubiquitination assay, substrate lysine identification, ALI mouse model with YOD1 deficiency","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct OTU-domain binding, K48 chain deubiquitination at defined lysines, in vivo KO model; single lab","pmids":["41326673"],"is_preprint":false},{"year":2025,"finding":"YOD1 deubiquitinates and stabilizes ZNF24 by its catalytic activity. YOD1-mediated ZNF24 stabilization maintains ZNF24 transcriptional repression of VEGFA gene expression. YOD1 knockdown leads to ZNF24 degradation and derepression of VEGFA, promoting ccRCC metastasis.","method":"RNAi screen, co-immunoprecipitation, ubiquitination assay (catalytic mutant dependence), patient-derived organoids, in vitro and in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased RNAi screen, direct binding and deubiquitination of ZNF24 confirmed, catalytic-activity dependence, in vivo validation; single lab","pmids":["40274778"],"is_preprint":false},{"year":2025,"finding":"YOD1 deubiquitinates and stabilizes PAX-FOXO1 and N-Myc oncoproteins in fusion-positive rhabdomyosarcoma. YOD1 knockdown or pharmacological inhibition with G5 promotes degradation of both PAX-FOXO1 and N-Myc, suppressing FP-RMS growth in vitro and in vivo.","method":"Co-immunoprecipitation, ubiquitination/stability assays, siRNA knockdown, pharmacological inhibitor (G5), in vitro and in vivo tumor models","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and deubiquitination of both substrates shown, in vivo validation; single lab","pmids":["41401084"],"is_preprint":false},{"year":2025,"finding":"YOD1 directly binds MAFbx via its UBX domain (interacting with the LZ domain of MAFbx) and stabilizes MAFbx by removing K48-linked polyubiquitin chains. YOD1 inhibition (pharmacological or genetic) destabilizes MAFbx and alleviates dexamethasone- and denervation-induced muscle atrophy in mouse models.","method":"siRNA DUB screen in C2C12 myotubes, domain-mapping co-immunoprecipitation (UBX-LZ interaction), K48 ubiquitin chain assay, pharmacological inhibitor (G5), in vivo mouse atrophy models, grip strength and fiber size measurements","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"High","confidence_rationale":"Tier 2 / Moderate — unbiased DUB screen, domain-level interaction mapping, K48 chain deubiquitination, multiple in vivo models with functional readouts; multiple orthogonal methods","pmids":["42052961"],"is_preprint":false},{"year":2025,"finding":"YOD1 stabilizes DNAJA1 through deubiquitination, promoting mitochondrial unfolded protein response (UPRmt) activation. YOD1 interaction with DNAJA1 was established by molecular docking, co-immunoprecipitation, and protein stability assays. Neuron-specific YOD1 overexpression preserved mitochondrial function and reduced neuronal apoptosis after subarachnoid hemorrhage.","method":"Molecular docking, co-immunoprecipitation, protein stability assay, flow cytometry (UPRmt+ vs UPRmt- neuron isolation), in vitro and in vivo SAH models, neuron-specific YOD1 overexpression","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular docking + Co-IP + stability assay for DNAJA1 deubiquitination, functional in vivo model; single lab","pmids":["42103167"],"is_preprint":false},{"year":2025,"finding":"In cardiomyocytes, YOD1 interacts with NLRP3 and deubiquitinates K48-linked ubiquitin chains on NLRP3 via its active site H262, blocking NLRP3 proteasomal degradation and promoting NLRP3 inflammasome activation and NLRP3-driven pyroptosis in septic cardiomyopathy. Cardiomyocyte-specific YOD1 KO alleviates septic cardiomyopathy; NLRP3 inhibition counteracts the protective effect of YOD1 KO.","method":"Transcriptome sequencing, co-immunoprecipitation with LC-MS/MS substrate ID, active-site mutagenesis (H262), K48 ubiquitin chain assay, cardiomyocyte-specific YOD1 KO mouse model, LPS/CLP sepsis models","journal":"British journal of pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — LC-MS/MS substrate ID, active-site mutagenesis, K48 chain deubiquitination, cardiomyocyte-specific KO in two in vivo sepsis models with NLRP3 rescue; multiple orthogonal methods","pmids":["41913386"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure shows that mammalian YOD1 (Otu1 in yeast) binds to p97 simultaneously with other Cdc48 cofactors. The DUB trims the ubiquitin chain of substrates before their translocation through the Cdc48/p97 pore is initiated, enabling substrate transfer to the proteasome for degradation and preventing futile cycles of re-translocation.","method":"Cryo-EM structure of YOD1/Otu1 bound to p97/Cdc48 complex, in vitro reconstitution, deubiquitination and translocation assays in yeast and mammalian systems","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure plus reconstituted biochemical assays; preprint not yet peer-reviewed, but method quality is Tier 1","pmids":["bio_10.1101_2025.11.08.687396"],"is_preprint":true},{"year":2025,"finding":"YOD1 directly binds PKM2 and removes K63-linked ubiquitin chains from PKM2, increasing the dimer-to-tetramer ratio (reducing tetramer formation) and inhibiting dimerized PKM2 nuclear entry, thereby regulating Nrf2-mediated antioxidant responses in a Parkinson's disease context. YOD1 KO ameliorates motor impairments and oxidative stress in 6-OHDA PD model mice.","method":"Co-immunoprecipitation with LC-MS/MS, K63 ubiquitin chain assay, PKM2 tetramer/dimer analysis, YOD1 KO mouse model (6-OHDA), behavioral assays, immunofluorescence","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LC-MS/MS substrate ID, K63 chain deubiquitination, functional tetramer assay, in vivo KO model; single lab (note: similar YOD1-PKM2 finding reported independently for cardiac context, providing some cross-context corroboration)","pmids":["40681475"],"is_preprint":false}],"current_model":"YOD1 (OTUD2/DUBA8) is an OTU-family deubiquitinating enzyme that associates with the p97/VCP AAA-ATPase via its UBX domain and acts through its catalytic OTU domain (active sites C160/H262) to trim ubiquitin chains on substrates prior to or during their retrotranslocation from the ER (ERAD) or release from ruptured lysosomes for autophagy; beyond this core p97-coupled function, YOD1 stabilizes or destabilizes a growing catalogue of substrates—including ITCH, LATS1/2 (Hippo), TRAF6/p62 (NF-κB), MAVS (innate immunity), STAT3, β-catenin, NLRP3, RIPK2, MYH9, CDK1, p53, TRIM33, ZNF24, MAFbx, PKM2, NCOA4, and DNAJA1—by removing K48-, K63-, or K33-linked ubiquitin chains from them, with functional consequences spanning ER quality control, lysosomal homeostasis, Hippo/YAP signaling, antiviral and inflammatory signaling, antigen cross-presentation, cardiac hypertrophy, neurodegeneration, and muscle atrophy."},"narrative":{"mechanistic_narrative":"YOD1 is an OTU-family deubiquitinating enzyme that functions as a p97/VCP-associated cofactor controlling protein quality control and, more broadly, sets the abundance and activity of numerous signaling proteins by editing their ubiquitin chains [PMID:19818707, PMID:bio_10.1101_2025.11.08.687396]. Its founding role is in ER-associated degradation: YOD1 associates with the p97 AAA-ATPase and its catalytic activity is required to dislocate misfolded proteins from the ER, with a catalytically inactive variant acting as a dominant negative that stabilizes substrates and accumulates polyubiquitinated intermediates on cytosolic p97 [PMID:19818707]. It participates in both retro-translocation-triggering and downstream deglycosylation/degradation steps depending on the substrate [PMID:26463207], and cryo-EM of the YOD1/Otu1–p97/Cdc48 complex shows the DUB trims substrate ubiquitin chains before pore translocation to enable transfer to the proteasome and prevent futile re-translocation cycles [PMID:bio_10.1101_2025.11.08.687396]. Beyond the ER, p97 recruits YOD1 together with UBXD1 and PLAA to damaged lysosomes, where it removes K48-linked conjugates to promote autophagic clearance of ruptured lysosomes [PMID:27753622]. Acting through its OTU catalytic core (active sites including C160, C155, and H262), YOD1 deubiquitinates a wide range of substrates and thereby tunes major signaling axes: it stabilizes the E3 ligase ITCH to drive LATS1/2 degradation and YAP/TAZ-dependent Hippo output and hepatomegaly [PMID:28416659], removes K63 chains from MAVS to dampen antiviral interferon signaling [PMID:30952814], and controls antigen retention for MHC class I cross-presentation [PMID:23243279]. A large body of work establishes YOD1 as a stabilizer of disease-relevant substrates by stripping K48-, K63-, or K33-linked chains, including STAT3, PKM2, and NLRP3 in cardiac hypertrophy and septic cardiomyopathy [PMID:40561034, PMID:40500343, PMID:41913386], RIPK2 in intestinal NOD2 signaling [PMID:39333628], MAFbx in muscle atrophy [PMID:42052961], β-catenin in endothelial-mesenchymal transition [PMID:38641745], and multiple oncoproteins and tumor regulators such as p53, CDK1, TRIM33, and ZNF24 [PMID:37667382, PMID:37454155, PMID:37573347, PMID:40274778].","teleology":[{"year":2009,"claim":"Established YOD1's foundational identity as a p97-associated OTU deubiquitinase whose catalytic activity is required to extract misfolded proteins from the ER, defining its core cellular role.","evidence":"Co-IP, dominant-negative catalytic mutant, ERAD substrate stabilization assays in mammalian cells","pmids":["19818707"],"confidence":"High","gaps":["Did not resolve direct ubiquitin chain linkage specificity in the ER context","Substrate repertoire beyond model ERAD clients unmapped"]},{"year":2012,"claim":"Showed YOD1 catalytic activity controls antigen processing, linking its DUB function to MHC class I cross-presentation in antigen-presenting cells.","evidence":"YOD1-C160S catalytic knock-in mouse, in vitro/in vivo cross-presentation and viral infection models, inhibitor treatments","pmids":["23243279"],"confidence":"High","gaps":["Direct substrate(s) deubiquitinated during antigen processing not identified","Relationship to p97/ERAD machinery in this context unclear"]},{"year":2015,"claim":"Dissected YOD1's ERAD role into two mechanistically distinct steps, showing its requirement varies by substrate (retro-translocation triggering vs. downstream degradation).","evidence":"In vivo biotinylation retro-translocation assay with multiple ERAD substrates under impaired p97/YOD1 activity","pmids":["26463207"],"confidence":"High","gaps":["Molecular basis for substrate-specific step requirement not resolved","Structural mechanism awaited"]},{"year":2016,"claim":"Extended the p97-YOD1 axis beyond the ER, establishing it as part of the ELDR module that clears damaged lysosomes by autophagy via K48 chain removal.","evidence":"Imaging, Co-IP, siRNA, linkage-specific ubiquitin analysis, p97-mutant MEFs and patient tissue","pmids":["27753622"],"confidence":"High","gaps":["Direct lysosomal substrate(s) of YOD1 not identified","Order of UBXD1/PLAA/YOD1 action incompletely defined"]},{"year":2017,"claim":"Connected YOD1 to Hippo and NF-κB signaling, showing it can act both catalytically (stabilizing ITCH to degrade LATS1/2) and non-catalytically (competing with p62 for TRAF6).","evidence":"siRNA screen, Co-IP, ubiquitination and competition assays, NF-κB reporters, inducible YOD1 transgenic mice","pmids":["28416659","28244869"],"confidence":"High","gaps":["Whether catalytic and non-catalytic modes operate in the same cells unclear","In vivo NF-κB consequences not tested with genetic models"]},{"year":2019,"claim":"Defined a substrate-direct antiviral role, with YOD1 removing K63 chains from MAVS to limit aggregation and interferon production.","evidence":"Mitochondrial fractionation, K63-specific ubiquitination assays, domain mapping, siRNA with IFN-β readouts in human and murine cells","pmids":["30952814"],"confidence":"High","gaps":["Trigger for YOD1 mitochondrial recruitment timing not fully defined","Physiological relevance in infected animals not established"]},{"year":2018,"claim":"Implicated YOD1 in proteostasis of neurodegeneration-associated aggregates, showing catalytically dependent clearance of mutant huntingtin and α-synuclein.","evidence":"In vitro K48/K63 DUB assay, catalytic mutant rescue, Lewy body immunofluorescence, stress induction","pmids":["29330040"],"confidence":"Medium","gaps":["Direct deubiquitination of the aggregating proteins vs. indirect effect not separated here","Single lab"]},{"year":2020,"claim":"Identified NEDD4 as a YOD1 target, linking K63-chain removal on this E3 ligase to control of cell proliferation.","evidence":"Co-IP, K63-specific ubiquitination assay, proliferation assay, UUO mouse DUB screen","pmids":["31916733"],"confidence":"Medium","gaps":["Downstream substrate consequences of NEDD4 stabilization not fully traced","Single lab"]},{"year":2023,"claim":"Expanded the substrate catalogue across cancer contexts, showing YOD1 stabilizes oncogenic and tumor-suppressive proteins (CDK1, p53, TRIM33, α-synuclein, USP21/MARK) by deubiquitination.","evidence":"Co-IP/domain mapping, proximity ligation, linkage-specific DUB assays, catalytic mutants, xenograft and tumor models across several labs","pmids":["37667382","37454155","37573347","36682332","37743467"],"confidence":"Medium","gaps":["Substrate selectivity determinants across these targets unexplained","Each link rests largely on a single study"]},{"year":2021,"claim":"Provided pharmacological tractability, showing YOD1 stabilizes the PML/RARα oncoprotein and that a small-molecule inhibitor (G5) eradicates APL cells.","evidence":"DUB siRNA screen, PML/RARα stability blots, G5 inhibitor in vivo and in patient-derived blasts","pmids":["35847510"],"confidence":"Medium","gaps":["Direct biochemical deubiquitination of PML/RARα not demonstrated","G5 selectivity for YOD1 not fully characterized"]},{"year":2024,"claim":"Established YOD1 as a driver of fibrotic, inflammatory, and neuroinflammatory disease via K48-chain removal on β-catenin, MYH9, and RIPK2, plus K33-chain editing of NLRP3.","evidence":"LC-MS/MS substrate ID, active-site/lysine mutagenesis, linkage-specific assays, YOD1 KO mice with disease and bone-marrow-transplant models","pmids":["38641745","40041897","38789414","39333628"],"confidence":"High","gaps":["Opposing effects on NLRP3 (K33 vs K48) across tissues not reconciled within single models","Cell-type specificity of substrate choice incompletely defined"]},{"year":2025,"claim":"Mapped detailed catalytic mechanism and structure: cryo-EM of the YOD1/Otu1-p97 complex plus active-site (C155/H262) and substrate-lysine mapping for STAT3, PKM2, NLRP3, NCOA4, ZNF24, MAFbx, DNAJA1, and fusion oncoproteins across cardiac, neuronal, muscle, and cancer disease models.","evidence":"Cryo-EM and reconstitution; proteomic substrate ID, active-site and substrate-lysine mutagenesis, linkage-specific assays, tissue-specific KO mice with pharmacological rescue","pmids":["40561034","40500343","41326673","40274778","42052961","42103167","41913386","40681475","bio_10.1101_2025.11.08.687396"],"confidence":"High","gaps":["What dictates linkage and lysine selectivity across this diverse substrate set is unresolved","Cryo-EM structure is a preprint","How a single DUB produces context-opposite outcomes (e.g. cardioprotective vs detrimental) not unified"]},{"year":null,"claim":"It remains unknown how YOD1's substrate, chain-linkage, and lysine selectivity are determined in vivo, and how its core p97/ERAD-lysosome function relates mechanistically to its many context-specific signaling substrates.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking p97-coupled chain trimming to free-standing substrate stabilization","Regulation of YOD1 recruitment to distinct organelles and substrates uncharacterized","Endogenous interactome and tissue-specific cofactor requirements not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,5,15,17,19,20,24,26]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,7,12,27]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,14]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,27]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,27]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,14,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5,6,17,18,26]}],"complexes":["p97/VCP-Otu1 complex","ELDR (p97-UBXD1-PLAA-YOD1)"],"partners":["VCP","ITCH","TRAF6","MAVS","NEDD4","USP21","NLRP3","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5VVQ6","full_name":"Ubiquitin thioesterase OTU1","aliases":["DUBA-8","HIV-1-induced protease 7","HIN-7","HsHIN7","OTU domain-containing protein 2"],"length_aa":348,"mass_kda":38.3,"function":"Hydrolase that can remove conjugated ubiquitin from proteins and participates in endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal proteins. May act by triming the ubiquitin chain on the associated substrate to facilitate their threading through the VCP/p97 pore. Ubiquitin moieties on substrates may present a steric impediment to the threading process when the substrate is transferred to the VCP pore and threaded through VCP's axial channel. Mediates deubiquitination of 'Lys-27'-, 'Lys-29'- and 'Lys-33'-linked polyubiquitin chains. Also able to hydrolyze 'Lys-11'-linked ubiquitin chains. Cleaves both polyubiquitin and di-ubiquitin. May play a role in macroautophagy, regulating for instance the clearance of damaged lysosomes. May recruit PLAA, UBXN6 and VCP to damaged lysosome membranes decorated with K48-linked ubiquitin chains and remove these chains allowing autophagosome formation (PubMed:27753622)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q5VVQ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YOD1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/YOD1","total_profiled":1310},"omim":[{"mim_id":"612023","title":"YOD1 DEUBIQUITINASE; YOD1","url":"https://www.omim.org/entry/612023"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":55.3}],"url":"https://www.proteinatlas.org/search/YOD1"},"hgnc":{"alias_symbol":["DKFZp451J1719","OTUD2","DUBA8"],"prev_symbol":[]},"alphafold":{"accession":"Q5VVQ6","domains":[{"cath_id":"3.10.20.90","chopping":"47-123","consensus_level":"high","plddt":86.8895,"start":47,"end":123},{"cath_id":"3.90.70.80","chopping":"149-308","consensus_level":"high","plddt":94.7894,"start":149,"end":308},{"cath_id":"-","chopping":"318-348","consensus_level":"high","plddt":89.371,"start":318,"end":348}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VVQ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VVQ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VVQ6-F1-predicted_aligned_error_v6.png","plddt_mean":80.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YOD1","jax_strain_url":"https://www.jax.org/strain/search?query=YOD1"},"sequence":{"accession":"Q5VVQ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5VVQ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5VVQ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VVQ6"}},"corpus_meta":[{"pmid":"27753622","id":"PMC_27753622","title":"VCP/p97 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<i>Drosophila</i>","date":"2025-07-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.24.666383","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25188,"output_tokens":8438,"usd":0.101067,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17970,"output_tokens":4624,"usd":0.102725,"stage2_stop_reason":"end_turn"},"total_usd":0.203792,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"YOD1 is a deubiquitinating enzyme of the OTU (otubain) family that associates with the p97 AAA-ATPase complex and its deubiquitinating activity is required for dislocation of misfolded proteins from the ER (ERAD). A catalytically inactive YOD1 variant acts as a dominant negative, stabilizing dislocation substrates and increasing polyubiquitinated intermediates associated with p97 in the cytosol. The dominant-negative effect depends on the UBX and Zinc finger domains flanking the catalytic OTU core.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative catalytic mutant expression, stabilization assay of ERAD substrates in mammalian cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, dominant-negative mutagenesis, multiple ERAD substrates tested; foundational study replicated by subsequent work\",\n      \"pmids\": [\"19818707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Both p97 and YOD1 participate in two distinct retro-translocation steps in ERAD: for substrates CD4 (Vpu-induced) and MHC-Iα (US2/US11-induced), they have a retro-translocation-triggering role, whereas for spontaneous ERAD substrates (NS1, NHK-α1AT, BST-2/Tetherin), they are required for downstream deglycosylation and proteasomal degradation steps.\",\n      \"method\": \"In vivo biotinylation retro-translocation assay in mammalian cells under impaired p97 or YOD1 activity, using multiple distinct ERAD substrates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct retro-translocation assay with multiple orthogonal substrates, single lab but rigorous mechanistic dissection\",\n      \"pmids\": [\"26463207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Upon lysosomal damage, p97 translocates to lysosomes and cooperates with cofactors UBXD1, PLAA, and YOD1 (termed ELDR components). Together they act downstream of K63-linked ubiquitination and p62 recruitment, and selectively remove K48-linked ubiquitin conjugates from damaged lysosomes to promote autophagosome formation, driving clearance of ruptured lysosomes by autophagy.\",\n      \"method\": \"Fluorescence imaging, co-immunoprecipitation, siRNA knockdown with lysosomal damage assay, lysosome-associated ubiquitin chain-linkage analysis, MEF p97-mutant model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (imaging, Co-IP, KO/KD, linkage-specific ubiquitin analysis), genetic disease patient tissue validation\",\n      \"pmids\": [\"27753622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YOD1 deubiquitinates ITCH (an E3 ligase targeting LATS1/2), enhancing ITCH protein stability. This leads to increased ITCH-mediated ubiquitination and degradation of LATS1/2, resulting in elevated YAP/TAZ levels and downstream Hippo pathway activation. Inducible YOD1 expression in transgenic mice causes hepatomegaly in a YAP/TAZ-dependent manner.\",\n      \"method\": \"siRNA screening, co-immunoprecipitation, ubiquitination assay, transgenic mouse model with inducible YOD1 expression, rescue experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA screen, biochemical ubiquitination assays, in vivo transgenic model with YAP/TAZ-dependent rescue, multiple orthogonal methods\",\n      \"pmids\": [\"28416659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YOD1 interacts with the C-terminal TRAF homology domain of TRAF6 and competes with the adaptor p62/Sequestosome-1 for TRAF6 binding. YOD1 inhibits TRAF6/p62-dependent IL-1 signaling to NF-κB by a non-catalytic mechanism: it prevents TRAF6 sequestration into cytosolic p62 aggregates. Upon IL-1β stimulation, YOD1 is released from TRAF6, facilitating TRAF6 auto-ubiquitination and NEMO/IKKγ substrate ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, competition binding assay, overexpression/depletion of YOD1, NF-κB reporter assays, IL-1β stimulation experiments in human cells\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, competition assay, gain/loss-of-function with pathway readouts, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"28244869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YOD1 is recruited to mitochondria to interact with MAVS (via its UBX and Znf domains) after viral infection. YOD1 cleaves K63-linked ubiquitin chains on MAVS and abrogates formation of prion-like MAVS aggregates, thereby attenuating IRF3, p65 activation, and IFN-β production. YOD1 knockdown potentiates antiviral innate immune signaling.\",\n      \"method\": \"Co-immunoprecipitation, mitochondrial fractionation, ubiquitination assay (K63-linkage specific), siRNA knockdown, IRF3/p65 activation assays, IFN-β measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical interaction and K63-deubiquitination demonstrated, domain mapping, KD with pathway readouts, two cell systems (human and murine)\",\n      \"pmids\": [\"30952814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"APCs expressing catalytically inactive YOD1 (C160S mutant) retain antigen longer and present exogenous antigens more efficiently to CD8+ T cells. Enhanced cross-presentation is TAP1-independent but sensitive to inhibitors of acidification and the proteasome, indicating YOD1 deubiquitylase activity controls antigen processing for MHC class I cross-presentation.\",\n      \"method\": \"Catalytic mutant knock-in mouse model (YOD1-C160S), in vitro and in vivo antigen cross-presentation assays, viral infection models, pharmacological inhibitor treatment\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant mouse model with in vivo viral challenge, multiple antigen/infection systems, mechanistic inhibitor experiments\",\n      \"pmids\": [\"23243279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"YOD1 exhibits deubiquitinating activity with preference for K48- and K63-linked ubiquitin chains. YOD1 reduces cytotoxicity of mutant huntingtin and mutant α-synuclein through efficient degradation of these proteins; this neuroprotective activity is abolished by a catalytically inactive YOD1 mutant. YOD1 is upregulated by proteotoxic stress and localizes to Lewy bodies in Parkinson's disease patient tissue.\",\n      \"method\": \"In vitro deubiquitination assay (K48/K63 chain preference), catalytically inactive mutant rescue experiments, immunofluorescence (Lewy body localization), stress induction assays\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro DUB assay with linkage specificity, catalytic mutant functional test, patient tissue localization; single lab\",\n      \"pmids\": [\"29330040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YOD1 binds to NEDD4 (an E3 ligase targeting LATS1) and deubiquitinates K63-linked polyubiquitin chains on NEDD4, stabilizing NEDD4 and suppressing NEDD4-induced cell proliferation in kidney cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K63-linkage specific), cell proliferation assay, mouse UUO model for DUB screening\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and K63-deubiquitination of NEDD4 shown biochemically, functional cell proliferation readout; single lab\",\n      \"pmids\": [\"31916733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YOD1 is a critical deubiquitinase that maintains the stability of the PML/RARα oncoprotein in APL cells. siRNA-mediated suppression of YOD1 promotes proteasomal degradation of PML/RARα. A small-molecule YOD1 inhibitor (G5) degrades PML/RARα and eradicates APL cells in vitro and prolongs survival in APL cell-bearing mice.\",\n      \"method\": \"DUB siRNA library screen, Western blot for PML/RARα stability, pharmacological inhibitor (G5), in vivo APL mouse model, primary patient-derived APL blasts\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased siRNA screen identifies YOD1, validated with pharmacological inhibitor in vivo and in primary patient cells; mechanistic link to ubiquitination inferred but deubiquitination of PML/RARα not directly demonstrated biochemically\",\n      \"pmids\": [\"35847510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YOD1 directly interacts with CDK1 and deubiquitinates CDK1, preventing its proteasomal degradation and upregulating CDK1 protein levels. This interaction depends on YOD1's catalytic activity. YOD1 knockdown reduces CDK1 expression and inhibits TNBC cell proliferation, migration, and cell cycle progression.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation, proximity ligation assay, immunofluorescence, Western blot, in vitro catalytic mutant experiments, in vivo xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by Co-IP and proximity ligation, catalytic-activity dependence shown, in vivo validation; single lab\",\n      \"pmids\": [\"37667382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YOD1 deubiquitinates p53 and stabilizes it through interaction between the N-terminus of p53 and the OTU domain of YOD1. Loss of YOD1 in AML leads to reduced p53 stability; YOD1 overexpression stabilizes p53, upregulates pro-apoptotic p53 target genes, and increases AML cell sensitivity to FLT3 inhibitors.\",\n      \"method\": \"Co-immunoprecipitation (domain mapping), ubiquitination assay, Western blot for p53 stability, reporter gene assay for miR-221/222 targeting of YOD1 3'UTR, overexpression/knockdown functional assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP with domain mapping, ubiquitination assay for p53, functional rescue; single lab\",\n      \"pmids\": [\"37454155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YOD1 directly interacts with α-synuclein and deubiquitinates K6-, K11-, K29-, K33-, and K63-linked polyubiquitin chains on α-synuclein. YOD1 destabilizes α-synuclein protein by also upregulating NEDD4, the E3 ligase responsible for α-synuclein degradation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deubiquitination assay with linkage-specific ubiquitin chains, Western blot for protein stability\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct binding and multi-linkage deubiquitination shown biochemically; single lab, single study\",\n      \"pmids\": [\"36682332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YOD1 inhibits HNSCC progression by deubiquitinating and stabilizing the E3 ligase TRIM33, thereby suppressing activation of the ERK/β-catenin pathway.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blot for TRIM33 stability, in vitro and in vivo tumor models, pathway activity readouts\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical deubiquitination of TRIM33, pathway readouts, in vivo validation; single lab\",\n      \"pmids\": [\"37573347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YOD1 interacts with USP21 (another DUB involved in Hippo signaling) and deubiquitinates MARK (microtubule-affinity regulating kinase). YOD1 and USP21 mutually deubiquitinate each other; YOD1 regulates USP21 protein stability (but USP21 does not regulate YOD1 stability). Combined YOD1 and USP21 activity synergistically modulates Hippo signaling and cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, immunocytochemistry, Western blot for protein stability, cell proliferation/colony assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and GST pull-down, mutual deubiquitination confirmed biochemically; single lab\",\n      \"pmids\": [\"37743467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YOD1 directly binds β-catenin via its OTU domain (with histidine 262 as the active site) and removes K48-linked ubiquitin chains from β-catenin, preventing its proteasomal degradation and stabilizing β-catenin protein. This promotes Ang II-induced endothelial-mesenchymal transition. YOD1 knockout reduces EndMT in Ang II-treated mice and HUVECs.\",\n      \"method\": \"LC-MS/MS proteomics, co-immunoprecipitation, active-site mutagenesis (H262), K48 ubiquitin chain assay, YOD1 knockout mouse model, HUVEC experiments\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LC-MS/MS substrate identification, Co-IP, active-site mutant, K48 chain deubiquitination assay, in vivo knockout validation; multiple orthogonal methods\",\n      \"pmids\": [\"38641745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YOD1 interacts with MYH9 (Myosin heavy chain 9) and stabilizes it by removing K48-linked ubiquitin chains, thereby mediating microglial polarization signaling. YOD1 knockout improves microglial migration, phagocytosis, and inflammatory responses, and ameliorates cognitive impairment in AD model mice.\",\n      \"method\": \"LC-MS/MS combined with co-immunoprecipitation for substrate identification, K48 ubiquitin chain assay, YOD1 knockout mouse model, behavioral/cognitive assays\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LC-MS/MS + Co-IP for substrate ID, K48 chain deubiquitination, in vivo KO model; single lab\",\n      \"pmids\": [\"40041897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YOD1 directly interacts with NLRP3 and removes K33-linked ubiquitin chains from NLRP3, inhibiting NLRP3 expression and inflammasome activation. YOD1 deficiency enhances NLRP3 inflammasome activation and disseminated intravascular coagulation in MRSA sepsis models both in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, K33-linkage specific ubiquitination assay, YOD1 knockout mouse model, in vitro/in vivo MRSA infection models, NLRP3 inhibitor rescue\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction and K33-deubiquitination of NLRP3 shown, in vivo KO model; single lab\",\n      \"pmids\": [\"38789414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YOD1 inhibits proteasomal degradation of RIPK2 by reducing K48 polyubiquitination of RIPK2, thereby increasing RIPK2 abundance and enhancing NOD2-mediated protective signaling in macrophages against DSS-induced colitis. YOD1-deficient mice are highly susceptible to DSS colitis, and this effect is derived from hematopoietic cells (shown by bone marrow transplantation).\",\n      \"method\": \"YOD1 knockout mouse model, bone marrow transplantation, co-immunoprecipitation, K48 ubiquitination assay of RIPK2, DSS colitis model, NOD2 ligand (MDP) rescue experiments\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct deubiquitination of RIPK2, genetic epistasis via KO and bone marrow transplant, in vivo rescue with NOD2 ligand; multiple orthogonal methods\",\n      \"pmids\": [\"39333628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YOD1 deubiquitinates STAT3 by removing K48-linked ubiquitin chains at K97 of STAT3 via the C155 active site of YOD1, stabilizing STAT3 and enhancing its nuclear translocation in cardiomyocytes under Ang II stimulation. Cardiomyocyte-specific YOD1 knockout reduces Ang II- and TAC-induced cardiac hypertrophy; STAT3 inhibition reverses the antihypertrophic effect of YOD1 deficiency.\",\n      \"method\": \"Multiple proteomic analyses for substrate identification, co-immunoprecipitation, active-site and substrate lysine mutagenesis (C155, K97), K48 ubiquitin chain assay, cardiomyocyte-specific YOD1 KO mouse model, nuclear translocation assay, in vivo hypertrophy models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic substrate ID, active-site mutagenesis, substrate lysine mapping, K48 chain deubiquitination, cardiomyocyte-specific KO in vivo with STAT3 inhibitor rescue; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"40561034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YOD1 directly binds PKM2 and selectively removes K63-linked polyubiquitin chains from PKM2 at K311 via its active site H262. This deubiquitination destabilizes PKM2 tetramers, inhibits mitochondrial oxidative phosphorylation (OXPHOS), and promotes cardiac hypertrophy. PKM2 activator TEPP-46 reverses YOD1 overexpression-induced hypertrophy and OXPHOS inhibition.\",\n      \"method\": \"Quantitative proteomic screening, co-immunoprecipitation, active-site mutagenesis (H262), substrate lysine mutagenesis (K311), K63 ubiquitin chain assay, PKM2 tetramer/dimer assay, cardiomyocyte-specific YOD1 KO mouse model, OXPHOS measurement, pharmacological rescue\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative proteomics, active-site and substrate lysine mutagenesis, K63 chain-specific deubiquitination, functional tetramer assay, in vivo CKO mouse model with pharmacological rescue; multiple orthogonal methods\",\n      \"pmids\": [\"40500343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YOD1 directly interacts with NCOA4 via its OTU domain and inhibits K48-linked ubiquitination at K343/K353 of NCOA4, thereby stabilizing NCOA4 and facilitating NCOA4-mediated autophagic degradation of ferritin heavy chain 1 (FTH1), promoting ferroptosis in acute lung injury.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping experiments (OTU domain), K48-linkage ubiquitination assay, substrate lysine identification, ALI mouse model with YOD1 deficiency\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct OTU-domain binding, K48 chain deubiquitination at defined lysines, in vivo KO model; single lab\",\n      \"pmids\": [\"41326673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YOD1 deubiquitinates and stabilizes ZNF24 by its catalytic activity. YOD1-mediated ZNF24 stabilization maintains ZNF24 transcriptional repression of VEGFA gene expression. YOD1 knockdown leads to ZNF24 degradation and derepression of VEGFA, promoting ccRCC metastasis.\",\n      \"method\": \"RNAi screen, co-immunoprecipitation, ubiquitination assay (catalytic mutant dependence), patient-derived organoids, in vitro and in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased RNAi screen, direct binding and deubiquitination of ZNF24 confirmed, catalytic-activity dependence, in vivo validation; single lab\",\n      \"pmids\": [\"40274778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YOD1 deubiquitinates and stabilizes PAX-FOXO1 and N-Myc oncoproteins in fusion-positive rhabdomyosarcoma. YOD1 knockdown or pharmacological inhibition with G5 promotes degradation of both PAX-FOXO1 and N-Myc, suppressing FP-RMS growth in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination/stability assays, siRNA knockdown, pharmacological inhibitor (G5), in vitro and in vivo tumor models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and deubiquitination of both substrates shown, in vivo validation; single lab\",\n      \"pmids\": [\"41401084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YOD1 directly binds MAFbx via its UBX domain (interacting with the LZ domain of MAFbx) and stabilizes MAFbx by removing K48-linked polyubiquitin chains. YOD1 inhibition (pharmacological or genetic) destabilizes MAFbx and alleviates dexamethasone- and denervation-induced muscle atrophy in mouse models.\",\n      \"method\": \"siRNA DUB screen in C2C12 myotubes, domain-mapping co-immunoprecipitation (UBX-LZ interaction), K48 ubiquitin chain assay, pharmacological inhibitor (G5), in vivo mouse atrophy models, grip strength and fiber size measurements\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased DUB screen, domain-level interaction mapping, K48 chain deubiquitination, multiple in vivo models with functional readouts; multiple orthogonal methods\",\n      \"pmids\": [\"42052961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YOD1 stabilizes DNAJA1 through deubiquitination, promoting mitochondrial unfolded protein response (UPRmt) activation. YOD1 interaction with DNAJA1 was established by molecular docking, co-immunoprecipitation, and protein stability assays. Neuron-specific YOD1 overexpression preserved mitochondrial function and reduced neuronal apoptosis after subarachnoid hemorrhage.\",\n      \"method\": \"Molecular docking, co-immunoprecipitation, protein stability assay, flow cytometry (UPRmt+ vs UPRmt- neuron isolation), in vitro and in vivo SAH models, neuron-specific YOD1 overexpression\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular docking + Co-IP + stability assay for DNAJA1 deubiquitination, functional in vivo model; single lab\",\n      \"pmids\": [\"42103167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In cardiomyocytes, YOD1 interacts with NLRP3 and deubiquitinates K48-linked ubiquitin chains on NLRP3 via its active site H262, blocking NLRP3 proteasomal degradation and promoting NLRP3 inflammasome activation and NLRP3-driven pyroptosis in septic cardiomyopathy. Cardiomyocyte-specific YOD1 KO alleviates septic cardiomyopathy; NLRP3 inhibition counteracts the protective effect of YOD1 KO.\",\n      \"method\": \"Transcriptome sequencing, co-immunoprecipitation with LC-MS/MS substrate ID, active-site mutagenesis (H262), K48 ubiquitin chain assay, cardiomyocyte-specific YOD1 KO mouse model, LPS/CLP sepsis models\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LC-MS/MS substrate ID, active-site mutagenesis, K48 chain deubiquitination, cardiomyocyte-specific KO in two in vivo sepsis models with NLRP3 rescue; multiple orthogonal methods\",\n      \"pmids\": [\"41913386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure shows that mammalian YOD1 (Otu1 in yeast) binds to p97 simultaneously with other Cdc48 cofactors. The DUB trims the ubiquitin chain of substrates before their translocation through the Cdc48/p97 pore is initiated, enabling substrate transfer to the proteasome for degradation and preventing futile cycles of re-translocation.\",\n      \"method\": \"Cryo-EM structure of YOD1/Otu1 bound to p97/Cdc48 complex, in vitro reconstitution, deubiquitination and translocation assays in yeast and mammalian systems\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure plus reconstituted biochemical assays; preprint not yet peer-reviewed, but method quality is Tier 1\",\n      \"pmids\": [\"bio_10.1101_2025.11.08.687396\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YOD1 directly binds PKM2 and removes K63-linked ubiquitin chains from PKM2, increasing the dimer-to-tetramer ratio (reducing tetramer formation) and inhibiting dimerized PKM2 nuclear entry, thereby regulating Nrf2-mediated antioxidant responses in a Parkinson's disease context. YOD1 KO ameliorates motor impairments and oxidative stress in 6-OHDA PD model mice.\",\n      \"method\": \"Co-immunoprecipitation with LC-MS/MS, K63 ubiquitin chain assay, PKM2 tetramer/dimer analysis, YOD1 KO mouse model (6-OHDA), behavioral assays, immunofluorescence\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LC-MS/MS substrate ID, K63 chain deubiquitination, functional tetramer assay, in vivo KO model; single lab (note: similar YOD1-PKM2 finding reported independently for cardiac context, providing some cross-context corroboration)\",\n      \"pmids\": [\"40681475\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YOD1 (OTUD2/DUBA8) is an OTU-family deubiquitinating enzyme that associates with the p97/VCP AAA-ATPase via its UBX domain and acts through its catalytic OTU domain (active sites C160/H262) to trim ubiquitin chains on substrates prior to or during their retrotranslocation from the ER (ERAD) or release from ruptured lysosomes for autophagy; beyond this core p97-coupled function, YOD1 stabilizes or destabilizes a growing catalogue of substrates—including ITCH, LATS1/2 (Hippo), TRAF6/p62 (NF-κB), MAVS (innate immunity), STAT3, β-catenin, NLRP3, RIPK2, MYH9, CDK1, p53, TRIM33, ZNF24, MAFbx, PKM2, NCOA4, and DNAJA1—by removing K48-, K63-, or K33-linked ubiquitin chains from them, with functional consequences spanning ER quality control, lysosomal homeostasis, Hippo/YAP signaling, antiviral and inflammatory signaling, antigen cross-presentation, cardiac hypertrophy, neurodegeneration, and muscle atrophy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YOD1 is an OTU-family deubiquitinating enzyme that functions as a p97/VCP-associated cofactor controlling protein quality control and, more broadly, sets the abundance and activity of numerous signaling proteins by editing their ubiquitin chains [#0, #27]. Its founding role is in ER-associated degradation: YOD1 associates with the p97 AAA-ATPase and its catalytic activity is required to dislocate misfolded proteins from the ER, with a catalytically inactive variant acting as a dominant negative that stabilizes substrates and accumulates polyubiquitinated intermediates on cytosolic p97 [#0]. It participates in both retro-translocation-triggering and downstream deglycosylation/degradation steps depending on the substrate [#1], and cryo-EM of the YOD1/Otu1–p97/Cdc48 complex shows the DUB trims substrate ubiquitin chains before pore translocation to enable transfer to the proteasome and prevent futile re-translocation cycles [#27]. Beyond the ER, p97 recruits YOD1 together with UBXD1 and PLAA to damaged lysosomes, where it removes K48-linked conjugates to promote autophagic clearance of ruptured lysosomes [#2]. Acting through its OTU catalytic core (active sites including C160, C155, and H262), YOD1 deubiquitinates a wide range of substrates and thereby tunes major signaling axes: it stabilizes the E3 ligase ITCH to drive LATS1/2 degradation and YAP/TAZ-dependent Hippo output and hepatomegaly [#3], removes K63 chains from MAVS to dampen antiviral interferon signaling [#5], and controls antigen retention for MHC class I cross-presentation [#6]. A large body of work establishes YOD1 as a stabilizer of disease-relevant substrates by stripping K48-, K63-, or K33-linked chains, including STAT3, PKM2, and NLRP3 in cardiac hypertrophy and septic cardiomyopathy [#19, #20, #26], RIPK2 in intestinal NOD2 signaling [#18], MAFbx in muscle atrophy [#24], \\u03b2-catenin in endothelial-mesenchymal transition [#15], and multiple oncoproteins and tumor regulators such as p53, CDK1, TRIM33, and ZNF24 [#10, #11, #13, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established YOD1's foundational identity as a p97-associated OTU deubiquitinase whose catalytic activity is required to extract misfolded proteins from the ER, defining its core cellular role.\",\n      \"evidence\": \"Co-IP, dominant-negative catalytic mutant, ERAD substrate stabilization assays in mammalian cells\",\n      \"pmids\": [\"19818707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve direct ubiquitin chain linkage specificity in the ER context\", \"Substrate repertoire beyond model ERAD clients unmapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed YOD1 catalytic activity controls antigen processing, linking its DUB function to MHC class I cross-presentation in antigen-presenting cells.\",\n      \"evidence\": \"YOD1-C160S catalytic knock-in mouse, in vitro/in vivo cross-presentation and viral infection models, inhibitor treatments\",\n      \"pmids\": [\"23243279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate(s) deubiquitinated during antigen processing not identified\", \"Relationship to p97/ERAD machinery in this context unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Dissected YOD1's ERAD role into two mechanistically distinct steps, showing its requirement varies by substrate (retro-translocation triggering vs. downstream degradation).\",\n      \"evidence\": \"In vivo biotinylation retro-translocation assay with multiple ERAD substrates under impaired p97/YOD1 activity\",\n      \"pmids\": [\"26463207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for substrate-specific step requirement not resolved\", \"Structural mechanism awaited\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the p97-YOD1 axis beyond the ER, establishing it as part of the ELDR module that clears damaged lysosomes by autophagy via K48 chain removal.\",\n      \"evidence\": \"Imaging, Co-IP, siRNA, linkage-specific ubiquitin analysis, p97-mutant MEFs and patient tissue\",\n      \"pmids\": [\"27753622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct lysosomal substrate(s) of YOD1 not identified\", \"Order of UBXD1/PLAA/YOD1 action incompletely defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected YOD1 to Hippo and NF-\\u03baB signaling, showing it can act both catalytically (stabilizing ITCH to degrade LATS1/2) and non-catalytically (competing with p62 for TRAF6).\",\n      \"evidence\": \"siRNA screen, Co-IP, ubiquitination and competition assays, NF-\\u03baB reporters, inducible YOD1 transgenic mice\",\n      \"pmids\": [\"28416659\", \"28244869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether catalytic and non-catalytic modes operate in the same cells unclear\", \"In vivo NF-\\u03baB consequences not tested with genetic models\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a substrate-direct antiviral role, with YOD1 removing K63 chains from MAVS to limit aggregation and interferon production.\",\n      \"evidence\": \"Mitochondrial fractionation, K63-specific ubiquitination assays, domain mapping, siRNA with IFN-\\u03b2 readouts in human and murine cells\",\n      \"pmids\": [\"30952814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for YOD1 mitochondrial recruitment timing not fully defined\", \"Physiological relevance in infected animals not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Implicated YOD1 in proteostasis of neurodegeneration-associated aggregates, showing catalytically dependent clearance of mutant huntingtin and \\u03b1-synuclein.\",\n      \"evidence\": \"In vitro K48/K63 DUB assay, catalytic mutant rescue, Lewy body immunofluorescence, stress induction\",\n      \"pmids\": [\"29330040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct deubiquitination of the aggregating proteins vs. indirect effect not separated here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified NEDD4 as a YOD1 target, linking K63-chain removal on this E3 ligase to control of cell proliferation.\",\n      \"evidence\": \"Co-IP, K63-specific ubiquitination assay, proliferation assay, UUO mouse DUB screen\",\n      \"pmids\": [\"31916733\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream substrate consequences of NEDD4 stabilization not fully traced\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded the substrate catalogue across cancer contexts, showing YOD1 stabilizes oncogenic and tumor-suppressive proteins (CDK1, p53, TRIM33, \\u03b1-synuclein, USP21/MARK) by deubiquitination.\",\n      \"evidence\": \"Co-IP/domain mapping, proximity ligation, linkage-specific DUB assays, catalytic mutants, xenograft and tumor models across several labs\",\n      \"pmids\": [\"37667382\", \"37454155\", \"37573347\", \"36682332\", \"37743467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate selectivity determinants across these targets unexplained\", \"Each link rests largely on a single study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided pharmacological tractability, showing YOD1 stabilizes the PML/RAR\\u03b1 oncoprotein and that a small-molecule inhibitor (G5) eradicates APL cells.\",\n      \"evidence\": \"DUB siRNA screen, PML/RAR\\u03b1 stability blots, G5 inhibitor in vivo and in patient-derived blasts\",\n      \"pmids\": [\"35847510\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical deubiquitination of PML/RAR\\u03b1 not demonstrated\", \"G5 selectivity for YOD1 not fully characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established YOD1 as a driver of fibrotic, inflammatory, and neuroinflammatory disease via K48-chain removal on \\u03b2-catenin, MYH9, and RIPK2, plus K33-chain editing of NLRP3.\",\n      \"evidence\": \"LC-MS/MS substrate ID, active-site/lysine mutagenesis, linkage-specific assays, YOD1 KO mice with disease and bone-marrow-transplant models\",\n      \"pmids\": [\"38641745\", \"40041897\", \"38789414\", \"39333628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Opposing effects on NLRP3 (K33 vs K48) across tissues not reconciled within single models\", \"Cell-type specificity of substrate choice incompletely defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped detailed catalytic mechanism and structure: cryo-EM of the YOD1/Otu1-p97 complex plus active-site (C155/H262) and substrate-lysine mapping for STAT3, PKM2, NLRP3, NCOA4, ZNF24, MAFbx, DNAJA1, and fusion oncoproteins across cardiac, neuronal, muscle, and cancer disease models.\",\n      \"evidence\": \"Cryo-EM and reconstitution; proteomic substrate ID, active-site and substrate-lysine mutagenesis, linkage-specific assays, tissue-specific KO mice with pharmacological rescue\",\n      \"pmids\": [\"40561034\", \"40500343\", \"41326673\", \"40274778\", \"42052961\", \"42103167\", \"41913386\", \"40681475\", \"bio_10.1101_2025.11.08.687396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What dictates linkage and lysine selectivity across this diverse substrate set is unresolved\", \"Cryo-EM structure is a preprint\", \"How a single DUB produces context-opposite outcomes (e.g. cardioprotective vs detrimental) not unified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how YOD1's substrate, chain-linkage, and lysine selectivity are determined in vivo, and how its core p97/ERAD-lysosome function relates mechanistically to its many context-specific signaling substrates.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking p97-coupled chain trimming to free-standing substrate stabilization\", \"Regulation of YOD1 recruitment to distinct organelles and substrates uncharacterized\", \"Endogenous interactome and tissue-specific cofactor requirements not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 5, 15, 17, 19, 20, 24, 26]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 7, 12, 27]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 27]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 27]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 14, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5, 6, 17, 18, 26]}\n    ],\n    \"complexes\": [\"p97/VCP-Otu1 complex\", \"ELDR (p97-UBXD1-PLAA-YOD1)\"],\n    \"partners\": [\"VCP\", \"ITCH\", \"TRAF6\", \"MAVS\", \"NEDD4\", \"USP21\", \"NLRP3\", \"STAT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}