{"gene":"UBXN1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2013,"finding":"UBXN1 inhibits RLR/MAVS-mediated antiviral signaling by binding to MAVS, interfering with MAVS oligomerization, and disrupting the MAVS/TRAF3/TRAF6 signalosome; UBXN1 is induced following viral infection and acts specifically on RNA-virus-induced (not TLR3, TLR4, or DNA-virus-induced) innate immune responses.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression in cell lines, viral infection assays (VSV, Sendai, WNV, dengue); reporter assays for IFN induction","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic depletion and overexpression with defined signaling phenotypes, multiple orthogonal methods, replicated across multiple viruses","pmids":["23545497"],"is_preprint":false},{"year":2010,"finding":"UBXN1 recognizes autoubiquitinated BRCA1 through a bipartite interaction: the UBA domain binds K6-linked polyubiquitin chains on BRCA1, while C-terminal sequences bind the BRCA1/BARD1 heterodimer in a ubiquitin-independent manner; UBXN1 binding dramatically reduces the E3 ligase activity of BRCA1/BARD1.","method":"Biochemical pulldown, Co-immunoprecipitation, in vitro ubiquitination assays, domain-mapping experiments with UBA and C-terminal UBXN1 fragments","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitination assay with domain mutagenesis plus Co-IP, multiple orthogonal methods in a single rigorous study","pmids":["20351172"],"is_preprint":false},{"year":2015,"finding":"UBXN1 is a negative regulator of TNFα-triggered NF-κB signaling: it interacts with cIAP1 (an E3 ligase for RIP1 in the TNFR1 complex), competitively blocks cIAP1 recruitment to TNFR1, and thereby inhibits RIP1 polyubiquitination; this mechanism is independent of VCP/p97 (p97 knockdown does not affect UBXN1-mediated NF-κB inhibition).","method":"siRNA screen (51 ubiquitin-associated domain proteins), Co-immunoprecipitation, overexpression/knockdown, NF-κB reporter assays, RIP1 ubiquitination assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with competitive binding assay, siRNA screen, downstream ubiquitination readout, negative result (VCP-independence) validated by orthogonal KD","pmids":["25681446"],"is_preprint":false},{"year":2010,"finding":"UBXN1 (SAKS1) acts as a p97 adaptor that negatively modulates ERAD: it requires both polyubiquitin binding (UBA domain) and p97 binding (UBX domain) to function, and polyubiquitin binding positively regulates the SAKS1–p97 association; SAKS1 also protects polyubiquitin chains from deubiquitinase activity (e.g., ataxin-3), thereby slowing ERAD substrate degradation.","method":"In vitro binding assays, ERAD substrate degradation assays, p97 interaction studies, deubiquitinase protection assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of p97 binding plus functional ERAD assay and DUB-protection assay, multiple orthogonal methods, single lab","pmids":["21135095"],"is_preprint":false},{"year":2018,"finding":"UBXN1 serves as the VCP adaptor in the BAG6 triage pathway: the VCP–UBXN1 complex recognizes ubiquitylated cytosolic proteins bound to the BAG6 complex prior to ER insertion (but not during ERAD); loss of VCP–UBXN1 causes inappropriate stabilization of ubiquitylated BAG6 clients and their accumulation in insoluble aggregates, sensitizing cells to proteotoxic stress.","method":"Co-immunoprecipitation, siRNA/KO cell lines, proteasomal degradation assays, protein aggregation/solubility fractionation, proteotoxic stress assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, KO with defined substrate-accumulation phenotype, solubility fractionation; multiple orthogonal methods in one study","pmids":["29685906"],"is_preprint":false},{"year":2021,"finding":"UBXN1 (SAKS1) is a VCP/p97 cofactor required for mitophagy initiation: upon mitochondrial depolarization and in a PRKN-dependent manner, UBXN1 translocates with VCP to mitochondria; UBXN1 physically interacts with PRKN via its UBX domain; loss of UBXN1 impairs VCP and PRKN recruitment to depolarized mitochondria, reduces mitophagic flux, and leads to accumulation of MFN2 in para-mitochondrial 'blobs', indicating UBXN1 facilitates MFN2 removal from the outer mitochondrial membrane downstream of PINK1.","method":"Live-cell imaging, mitochondrial fractionation, Co-immunoprecipitation (UBX-domain-dependent PRKN interaction), siRNA/KO cell lines, mitophagy flux assays, domain-mapping (UBX deletion)","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence, reciprocal Co-IP with domain mapping, KO with defined mitophagy phenotypes, multiple orthogonal methods","pmids":["33966597"],"is_preprint":false},{"year":2021,"finding":"UBXN1 is required for aggresome formation: UBXN1 is recruited to aggresomes upon proteasome inhibition; UBXN1-knockout cells cannot form aggresomes and show increased Huntingtin polyQ inclusion bodies in mammalian cells and in a C. elegans Huntington's disease model; the p97–UBXN1 complex mediates aggresome formation and clearance.","method":"KO cell lines, immunofluorescence/live imaging of aggresome formation, C. elegans genetic model, siRNA, proteasome inhibition assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO with defined cellular phenotype (aggresome formation defect), confirmed in two model systems (mammalian and C. elegans), direct localization by imaging","pmids":["33712450"],"is_preprint":false},{"year":2024,"finding":"UBXN1 is a negative regulator of the unfolded protein response (UPR) and ER proteostasis: loss of UBXN1 activates the UPR, upregulates ER quality-control proteins, and increases translation in both resting and ER-stressed cells; this translational repression function is independent of p97.","method":"KO cell lines, quantitative proteomics, UPR reporter assays, translation assays, epistasis with p97 inhibition","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO with quantitative proteomics plus functional UPR/translation assays plus p97-independent epistasis, multiple orthogonal methods","pmids":["38177917"],"is_preprint":false},{"year":2020,"finding":"The extended UBA domain of UBXN1 specifically recognizes K6-linked diubiquitin: a C-terminally extended form of the UBA domain confers K6-linkage specificity, converging the two solution conformations of K6 diUb into a single conformation upon binding; the non-extended UBA domain does not show linkage preference.","method":"NMR spectroscopy with 15N-labeled synthetic diubiquitins, chemical shift perturbation, structural analysis","journal":"Frontiers in chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural determination with domain-specific variant comparison, rigorous biophysical method with functional interpretation","pmids":["32039147"],"is_preprint":false},{"year":2016,"finding":"UBA-UBX proteins p47 and SAKS1 (UBXN1) have opposing roles in ERAD substrate degradation: p47 promotes degradation of α-TCR while SAKS1 delays it; SAKS1 selectively inhibits degradation of ERAD substrates without affecting cytosolic proteasomal substrates; expression of SAKS1 is reduced in cells stably expressing ERAD substrates and elevated upon ER stress.","method":"ERAD substrate degradation assays (α-TCR, α1-antitrypsin, δCD3), siRNA knockdown, pulse-chase/cycloheximide chase, stable cell lines expressing ERAD substrates","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional degradation assay with KD, single lab, single method per substrate","pmids":["27785701"],"is_preprint":false},{"year":2024,"finding":"UBXN1 promotes noncanonical inflammasome activation: together with unanchored K48/K63-linked polyubiquitin chains, UBXN1 binds caspase-4/11, promoting their assembly and activation; UBXN1 deficiency impairs caspase-4/11 activation, cytokine secretion, and pyroptosis in response to intracellular LPS; UBXN1-deficient mice are protected from LPS- and CLP-induced sepsis.","method":"Co-immunoprecipitation (UBXN1–caspase-4/11 interaction), KO cell lines and mice, inflammasome activation assays, recombinant USP5 depletion of unanchored polyUb, USP5 inhibitor experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional in-cell and in-vivo readouts plus chemical perturbation; preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.10.30.621131"],"is_preprint":true},{"year":2024,"finding":"UBR5 mediates Lys11-linked polyubiquitination and degradation of UBXN1 downstream of SUB1/PC4, thereby activating NF-κB signaling; SUB1 interacts with UBR5 and increases its protein level, leading to reduced UBXN1 and consequently elevated NF-κB activity.","method":"Co-immunoprecipitation (SUB1–UBR5 interaction), ubiquitination assays (Lys11 linkage), KO/knockdown, NF-κB reporter assays, in vivo tumor models","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with ubiquitination linkage determination and functional downstream readout; single lab","pmids":["38240906"],"is_preprint":false},{"year":2021,"finding":"YTHDF2 accelerates UBXN1 mRNA degradation via METTL3-mediated m6A modification, leading to reduced UBXN1 protein and consequent NF-κB activation; UBXN1 overexpression attenuates the oncogenic effect of YTHDF2 overexpression.","method":"RNA immunoprecipitation (RIP), methylated RIP (MeRIP), RNA stability assays, siRNA knockdown/overexpression, orthotopic xenograft models","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and MeRIP establish m6A-dependent binding, RNA stability assay confirms mRNA decay; single lab with multiple orthogonal methods","pmids":["34246306"],"is_preprint":false},{"year":2021,"finding":"The lncRNA PRADX recruits the PRC2/DDX5 complex to the UBXN1 gene promoter, increasing H3K27 trimethylation and suppressing UBXN1 transcription, which in turn promotes NF-κB activity.","method":"ChIRP (chromatin isolation by RNA purification), ChIP, Co-IP, siRNA knockdown, H3K27me3 ChIP at UBXN1 promoter, xenograft models","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIRP and ChIP establish lncRNA–chromatin interaction at UBXN1 locus; functional downstream readout; single lab","pmids":["33754075"],"is_preprint":false},{"year":2024,"finding":"UBXN1 interacts with the inner mitochondrial membrane protein prohibitin (PHB) and sustains PHB expression; UBXN1 inhibition triggers mitochondrial damage and HCC cell apoptosis, indicating a role in maintaining mitochondrial homeostasis.","method":"Co-immunoprecipitation (UBXN1–PHB), KO/knockdown, apoptosis assays (TUNEL, FACS), mouse liver tumor models (Sleeping Beauty transposon)","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with in vivo phenotype, single lab, single binding method","pmids":["38773518"],"is_preprint":false},{"year":2019,"finding":"UBXN1 interacts with the TGEV coronavirus S1 spike protein and positively supports viral replication; UBXN1 knockdown reduces viral titer and S1 expression while overexpression increases viral copy number; UBXN1 negatively regulates IFN-β expression after TGEV infection.","method":"Yeast two-hybrid, GST pulldown, Co-immunoprecipitation, siRNA knockdown, overexpression, viral titer assays","journal":"Veterinary research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — initial interaction identified by yeast two-hybrid and pulldown, functional data from single lab; porcine virus model with limited mechanistic depth","pmids":["31029162"],"is_preprint":false}],"current_model":"UBXN1 is a multifunctional UBA-UBX domain protein that acts as a VCP/p97 cofactor and ubiquitin reader: its UBA domain specifically recognizes K6-linked polyubiquitin (e.g., on autoubiquitinated BRCA1) to inhibit BRCA1/BARD1 E3 ligase activity, while its UBX domain engages p97 to mediate triage of ubiquitylated BAG6 clients, ERAD substrate selectivity, aggresome formation, and MFN2 removal from mitochondria during PRKN-dependent mitophagy; independently of p97, UBXN1 represses translation to maintain ER proteostasis, negatively regulates TNFα-triggered NF-κB signaling by competitively blocking cIAP1 recruitment to TNFR1 and inhibiting RIP1 polyubiquitination, suppresses RLR/MAVS-mediated antiviral interferon responses by disrupting the MAVS/TRAF3/TRAF6 signalosome, and promotes noncanonical inflammasome activation by binding caspase-4/11 together with unanchored K48/K63-linked polyubiquitin chains; UBXN1 expression is itself regulated at multiple levels including METTL3/YTHDF2-dependent m6A mRNA decay, PRC2-mediated H3K27 methylation at its promoter, and UBR5-mediated Lys11-linked ubiquitination and degradation."},"narrative":{"mechanistic_narrative":"UBXN1 is a UBA-UBX domain protein that functions both as a VCP/p97 cofactor and as a linkage-selective ubiquitin reader controlling protein quality control and innate immune signaling [PMID:21135095, PMID:20351172]. Its extended UBA domain confers specificity for K6-linked polyubiquitin, collapsing the two solution conformations of K6 diubiquitin into a single bound conformation [PMID:32039147]; through this activity UBXN1 recognizes autoubiquitinated BRCA1 and, via additional ubiquitin-independent contacts to the BRCA1/BARD1 heterodimer, sharply represses its E3 ligase activity [PMID:20351172]. As a p97 adaptor it requires both polyubiquitin binding (UBA) and p97 binding (UBX), and couples ubiquitin recognition to triage of clients: it negatively modulates ERAD by protecting polyubiquitin chains from deubiquitinases and delaying substrate degradation [PMID:21135095, PMID:27785701], directs the VCP-dependent disposal of ubiquitylated BAG6 clients prior to ER insertion [PMID:29685906], is required for aggresome formation and clearance of polyQ inclusions [PMID:33712450], and translocates with VCP to depolarized mitochondria during PRKN-dependent mitophagy to facilitate MFN2 removal [PMID:33966597]. Independently of p97, UBXN1 represses translation to restrain the unfolded protein response and maintain ER proteostasis [PMID:38177917]. UBXN1 also acts as a negative regulator of inflammatory and antiviral signaling: it blocks cIAP1 recruitment to TNFR1 to limit RIP1 polyubiquitination and NF-κB activation [PMID:25681446], and binds MAVS to disrupt the MAVS/TRAF3/TRAF6 signalosome and dampen RNA-virus-induced interferon responses [PMID:23545497]. Consistent with its role as a signaling brake, UBXN1 abundance is suppressed at multiple levels—METTL3/YTHDF2-dependent m6A mRNA decay [PMID:34246306], PRC2-mediated H3K27 trimethylation at its promoter [PMID:33754075], and UBR5-mediated Lys11-linked ubiquitination and degradation [PMID:38240906]—each releasing NF-κB activity.","teleology":[{"year":2010,"claim":"Established UBXN1 as a linkage-selective ubiquitin reader that suppresses an E3 ligase, defining a non-degradative function for its UBA domain.","evidence":"Biochemical pulldown, in vitro ubiquitination, and domain mapping showing UBA binding to K6-polyUb on BRCA1 plus ubiquitin-independent BRCA1/BARD1 contacts that reduce ligase activity","pmids":["20351172"],"confidence":"High","gaps":["Cellular consequences for BRCA1-dependent DNA repair not established","Stoichiometry of inhibition unresolved"]},{"year":2010,"claim":"Defined UBXN1 as a bona fide p97 adaptor whose ubiquitin and p97 binding cooperate, and showed it negatively tunes ERAD by shielding chains from deubiquitination.","evidence":"In vitro p97 binding assays, ERAD substrate degradation assays, and deubiquitinase (ataxin-3) protection assays","pmids":["21135095"],"confidence":"High","gaps":["Which ERAD substrates are physiologically affected not defined","Mechanism of chain protection structurally unresolved"]},{"year":2013,"claim":"Showed UBXN1 acts as a virus-induced brake on RLR/MAVS antiviral signaling, distinguishing RNA-virus-specific suppression from TLR/DNA-virus pathways.","evidence":"Reciprocal Co-IP, siRNA/overexpression, and IFN reporter assays across multiple RNA viruses","pmids":["23545497"],"confidence":"High","gaps":["Whether ubiquitin-binding or p97 is required for MAVS regulation not addressed","In vivo antiviral relevance untested"]},{"year":2015,"claim":"Identified a p97-independent role for UBXN1 in restraining NF-κB by competitively blocking cIAP1 recruitment to TNFR1.","evidence":"siRNA screen, competitive Co-IP, RIP1 ubiquitination and NF-κB reporter assays, with VCP knockdown ruling out p97 dependence","pmids":["25681446"],"confidence":"High","gaps":["Structural basis of cIAP1 competition unknown","Whether ubiquitin binding contributes not resolved"]},{"year":2016,"claim":"Distinguished UBXN1 from other UBA-UBX proteins functionally, showing it selectively delays ERAD substrate degradation and is stress-regulated.","evidence":"ERAD substrate degradation assays with multiple substrates and siRNA knockdown comparing p47 and SAKS1","pmids":["27785701"],"confidence":"Medium","gaps":["Single method per substrate","Mechanistic basis for substrate selectivity not defined"]},{"year":2018,"claim":"Placed UBXN1 in the BAG6 triage pathway as the VCP adaptor handling ubiquitylated cytosolic clients before ER insertion, distinct from ERAD.","evidence":"Reciprocal Co-IP, KO cell lines, degradation assays, and solubility fractionation with proteotoxic stress assays","pmids":["29685906"],"confidence":"High","gaps":["Client repertoire incompletely mapped","How triage versus ERAD is discriminated unknown"]},{"year":2020,"claim":"Provided the structural basis for K6-linkage selectivity, showing a C-terminally extended UBA domain enforces specificity.","evidence":"NMR with 15N-labeled synthetic diubiquitins comparing extended versus non-extended UBA constructs","pmids":["32039147"],"confidence":"High","gaps":["Full-length protein conformation not solved","Cellular K6-chain ligands beyond BRCA1 not catalogued"]},{"year":2021,"claim":"Extended UBXN1's quality-control role to organelle clearance, defining it as a VCP cofactor for aggresome formation and for PRKN-dependent mitophagy.","evidence":"KO cell lines, imaging, C. elegans HD model, mitochondrial fractionation, UBX-domain-dependent PRKN Co-IP, and mitophagy flux assays","pmids":["33712450","33966597"],"confidence":"High","gaps":["Direct ubiquitin substrates at aggresomes/mitochondria not all defined","Relationship between aggresome and mitophagy functions unclear"]},{"year":2021,"claim":"Revealed UBXN1 is a transcriptionally and post-transcriptionally suppressed NF-κB brake, via m6A-driven mRNA decay and PRC2-mediated promoter silencing.","evidence":"MeRIP/RIP and RNA stability assays (METTL3/YTHDF2); ChIRP/ChIP at the UBXN1 promoter (PRADX/PRC2/DDX5); NF-κB reporters and xenografts","pmids":["34246306","33754075"],"confidence":"Medium","gaps":["Direct effect on NF-κB independent of confounding pathways not fully isolated","Tissue specificity of regulation unclear"]},{"year":2024,"claim":"Identified UBR5 as an E3 that degrades UBXN1 via Lys11-linked ubiquitination downstream of SUB1, closing a regulatory loop releasing NF-κB.","evidence":"Co-IP, Lys11-linkage ubiquitination assays, knockdown, NF-κB reporters, and in vivo tumor models","pmids":["38240906"],"confidence":"Medium","gaps":["UBR5 degron on UBXN1 not mapped","Single-lab finding"]},{"year":2024,"claim":"Defined a p97-independent role for UBXN1 in repressing translation to restrain the UPR and maintain ER proteostasis.","evidence":"KO cells with quantitative proteomics, UPR reporters, translation assays, and p97-inhibition epistasis","pmids":["38177917"],"confidence":"High","gaps":["Molecular mechanism of translational repression unknown","Direct effectors of translation control unidentified"]},{"year":2024,"claim":"Implicated UBXN1 as a positive regulator of noncanonical inflammasome activation through caspase-4/11 binding with unanchored polyubiquitin.","evidence":"Co-IP, KO cells and mice, inflammasome/pyroptosis assays, and USP5-based depletion of unanchored polyUb (preprint)","pmids":["bio_10.1101_2024.10.30.621131"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","How a negative NF-κB regulator positively drives inflammasomes mechanistically unresolved"]},{"year":2024,"claim":"Linked UBXN1 to mitochondrial homeostasis through interaction with prohibitin and support of HCC cell survival.","evidence":"Co-IP, KO/knockdown, apoptosis assays, and Sleeping Beauty mouse liver tumor models","pmids":["38773518"],"confidence":"Medium","gaps":["Single binding method","Mechanism by which UBXN1 sustains PHB expression unknown"]},{"year":null,"claim":"How UBXN1 integrates its dual identity—p97-coupled quality-control adaptor versus p97-independent signaling/translation regulator—into a coherent regulatory logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking ubiquitin-linkage selectivity to specific cellular outputs","Determinants of when UBXN1 engages p97 versus acts independently unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,0,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4,5]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,6]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,7,9]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5,14]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,4,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,0]}],"complexes":["VCP/p97-UBXN1 complex","BAG6 complex"],"partners":["VCP","BRCA1","BARD1","MAVS","BIRC2","PRKN","BAG6","PHB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q04323","full_name":"UBX domain-containing protein 1","aliases":["SAPK substrate protein 1","UBA/UBX 33.3 kDa protein"],"length_aa":297,"mass_kda":33.3,"function":"Ubiquitin-binding protein that plays a role in the modulation of innate immune response. Blocks both the RIG-I-like receptors (RLR) and NF-kappa-B pathways. Following viral infection, UBXN1 is induced and recruited to the RLR component MAVS. In turn, interferes with MAVS oligomerization, and disrupts the MAVS/TRAF3/TRAF6 signalosome. This function probably serves as a brake to prevent excessive RLR signaling (PubMed:23545497). Interferes with the TNFalpha-triggered NF-kappa-B pathway by interacting with cellular inhibitors of apoptosis proteins (cIAPs) and thereby inhibiting their recruitment to TNFR1 (PubMed:25681446). Also prevents the activation of NF-kappa-B by associating with CUL1 and thus inhibiting NF-kappa-B inhibitor alpha/NFKBIA degradation that remains bound to NF-kappa-B (PubMed:28152074). Interacts with the BRCA1-BARD1 heterodimer and regulates its activity. Specifically binds 'Lys-6'-linked polyubiquitin chains. Interaction with autoubiquitinated BRCA1 leads to the inhibition of the E3 ubiquitin-protein ligase activity of the BRCA1-BARD1 heterodimer (PubMed:20351172). Component of a complex required to couple deglycosylation and proteasome-mediated degradation of misfolded proteins in the endoplasmic reticulum that are retrotranslocated in the cytosol","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q04323/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBXN1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UBXN1","total_profiled":1310},"omim":[{"mim_id":"616378","title":"UBX DOMAIN PROTEIN 1; UBXN1","url":"https://www.omim.org/entry/616378"},{"mim_id":"609676","title":"MITOCHONDRIAL ANTIVIRAL SIGNALING PROTEIN; MAVS","url":"https://www.omim.org/entry/609676"},{"mim_id":"113705","title":"BRCA1 DNA REPAIR-ASSOCIATED PROTEIN; BRCA1","url":"https://www.omim.org/entry/113705"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UBXN1"},"hgnc":{"alias_symbol":["LOC51035","2B28","UBXD10","SAKS1"],"prev_symbol":[]},"alphafold":{"accession":"Q04323","domains":[{"cath_id":"3.10.20.90","chopping":"212-247_256-292","consensus_level":"high","plddt":90.8634,"start":212,"end":292}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04323","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q04323-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q04323-F1-predicted_aligned_error_v6.png","plddt_mean":76.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBXN1","jax_strain_url":"https://www.jax.org/strain/search?query=UBXN1"},"sequence":{"accession":"Q04323","fasta_url":"https://rest.uniprot.org/uniprotkb/Q04323.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q04323/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04323"}},"corpus_meta":[{"pmid":"34246306","id":"PMC_34246306","title":"YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m6A modification to activate NF-κB and promote the malignant progression of glioma.","date":"2021","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34246306","citation_count":146,"is_preprint":false},{"pmid":"23545497","id":"PMC_23545497","title":"UBXN1 interferes with Rig-I-like receptor-mediated antiviral immune response by targeting MAVS.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23545497","citation_count":58,"is_preprint":false},{"pmid":"33754075","id":"PMC_33754075","title":"LncRNA PRADX-mediated recruitment of PRC2/DDX5 complex suppresses UBXN1 expression and activates NF-κB activity, promoting tumorigenesis.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/33754075","citation_count":53,"is_preprint":false},{"pmid":"20351172","id":"PMC_20351172","title":"The UBXN1 protein associates with autoubiquitinated forms of the BRCA1 tumor suppressor and inhibits its enzymatic function.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20351172","citation_count":49,"is_preprint":false},{"pmid":"27998759","id":"PMC_27998759","title":"The CRISPR/Cas9 system targeting EGFR exon 17 abrogates NF-κB activation via epigenetic modulation of UBXN1 in EGFRwt/vIII glioma cells.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/27998759","citation_count":36,"is_preprint":false},{"pmid":"25681446","id":"PMC_25681446","title":"Ubiquitin-associated domain-containing ubiquitin regulatory X (UBX) protein UBXN1 is a negative regulator of nuclear factor κB (NF-κB) signaling.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25681446","citation_count":33,"is_preprint":false},{"pmid":"33966597","id":"PMC_33966597","title":"VCP/p97 cofactor UBXN1/SAKS1 regulates mitophagy by modulating MFN2 removal from mitochondria.","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/33966597","citation_count":32,"is_preprint":false},{"pmid":"21135095","id":"PMC_21135095","title":"The UBX protein SAKS1 negatively regulates endoplasmic reticulum-associated degradation and p97-dependent degradation.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21135095","citation_count":29,"is_preprint":false},{"pmid":"29685906","id":"PMC_29685906","title":"The VCP-UBXN1 Complex Mediates Triage of Ubiquitylated Cytosolic Proteins Bound to the BAG6 Complex.","date":"2018","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29685906","citation_count":27,"is_preprint":false},{"pmid":"33508783","id":"PMC_33508783","title":"CircMRE11A_013 binds to UBXN1 and integrates ATM activation enhancing lens epithelial cells senescence in age-related cataract.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33508783","citation_count":24,"is_preprint":false},{"pmid":"33712450","id":"PMC_33712450","title":"The p97-UBXN1 complex regulates aggresome formation.","date":"2021","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/33712450","citation_count":19,"is_preprint":false},{"pmid":"27785701","id":"PMC_27785701","title":"The opposite role of two UBA-UBX containing proteins, p47 and SAKS1 in the degradation of a single ERAD substrate, α-TCR.","date":"2016","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27785701","citation_count":11,"is_preprint":false},{"pmid":"38240906","id":"PMC_38240906","title":"SUB1 promotes colorectal cancer metastasis by activating NF-κB signaling via UBR5-mediated ubiquitination of UBXN1.","date":"2024","source":"Science China. 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UBXN1 is induced following viral infection and acts specifically on RNA-virus-induced (not TLR3, TLR4, or DNA-virus-induced) innate immune responses.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression in cell lines, viral infection assays (VSV, Sendai, WNV, dengue); reporter assays for IFN induction\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic depletion and overexpression with defined signaling phenotypes, multiple orthogonal methods, replicated across multiple viruses\",\n      \"pmids\": [\"23545497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UBXN1 recognizes autoubiquitinated BRCA1 through a bipartite interaction: the UBA domain binds K6-linked polyubiquitin chains on BRCA1, while C-terminal sequences bind the BRCA1/BARD1 heterodimer in a ubiquitin-independent manner; UBXN1 binding dramatically reduces the E3 ligase activity of BRCA1/BARD1.\",\n      \"method\": \"Biochemical pulldown, Co-immunoprecipitation, in vitro ubiquitination assays, domain-mapping experiments with UBA and C-terminal UBXN1 fragments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitination assay with domain mutagenesis plus Co-IP, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"20351172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"UBXN1 is a negative regulator of TNFα-triggered NF-κB signaling: it interacts with cIAP1 (an E3 ligase for RIP1 in the TNFR1 complex), competitively blocks cIAP1 recruitment to TNFR1, and thereby inhibits RIP1 polyubiquitination; this mechanism is independent of VCP/p97 (p97 knockdown does not affect UBXN1-mediated NF-κB inhibition).\",\n      \"method\": \"siRNA screen (51 ubiquitin-associated domain proteins), Co-immunoprecipitation, overexpression/knockdown, NF-κB reporter assays, RIP1 ubiquitination assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with competitive binding assay, siRNA screen, downstream ubiquitination readout, negative result (VCP-independence) validated by orthogonal KD\",\n      \"pmids\": [\"25681446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UBXN1 (SAKS1) acts as a p97 adaptor that negatively modulates ERAD: it requires both polyubiquitin binding (UBA domain) and p97 binding (UBX domain) to function, and polyubiquitin binding positively regulates the SAKS1–p97 association; SAKS1 also protects polyubiquitin chains from deubiquitinase activity (e.g., ataxin-3), thereby slowing ERAD substrate degradation.\",\n      \"method\": \"In vitro binding assays, ERAD substrate degradation assays, p97 interaction studies, deubiquitinase protection assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of p97 binding plus functional ERAD assay and DUB-protection assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"21135095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"UBXN1 serves as the VCP adaptor in the BAG6 triage pathway: the VCP–UBXN1 complex recognizes ubiquitylated cytosolic proteins bound to the BAG6 complex prior to ER insertion (but not during ERAD); loss of VCP–UBXN1 causes inappropriate stabilization of ubiquitylated BAG6 clients and their accumulation in insoluble aggregates, sensitizing cells to proteotoxic stress.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/KO cell lines, proteasomal degradation assays, protein aggregation/solubility fractionation, proteotoxic stress assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, KO with defined substrate-accumulation phenotype, solubility fractionation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"29685906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UBXN1 (SAKS1) is a VCP/p97 cofactor required for mitophagy initiation: upon mitochondrial depolarization and in a PRKN-dependent manner, UBXN1 translocates with VCP to mitochondria; UBXN1 physically interacts with PRKN via its UBX domain; loss of UBXN1 impairs VCP and PRKN recruitment to depolarized mitochondria, reduces mitophagic flux, and leads to accumulation of MFN2 in para-mitochondrial 'blobs', indicating UBXN1 facilitates MFN2 removal from the outer mitochondrial membrane downstream of PINK1.\",\n      \"method\": \"Live-cell imaging, mitochondrial fractionation, Co-immunoprecipitation (UBX-domain-dependent PRKN interaction), siRNA/KO cell lines, mitophagy flux assays, domain-mapping (UBX deletion)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence, reciprocal Co-IP with domain mapping, KO with defined mitophagy phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"33966597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UBXN1 is required for aggresome formation: UBXN1 is recruited to aggresomes upon proteasome inhibition; UBXN1-knockout cells cannot form aggresomes and show increased Huntingtin polyQ inclusion bodies in mammalian cells and in a C. elegans Huntington's disease model; the p97–UBXN1 complex mediates aggresome formation and clearance.\",\n      \"method\": \"KO cell lines, immunofluorescence/live imaging of aggresome formation, C. elegans genetic model, siRNA, proteasome inhibition assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined cellular phenotype (aggresome formation defect), confirmed in two model systems (mammalian and C. elegans), direct localization by imaging\",\n      \"pmids\": [\"33712450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBXN1 is a negative regulator of the unfolded protein response (UPR) and ER proteostasis: loss of UBXN1 activates the UPR, upregulates ER quality-control proteins, and increases translation in both resting and ER-stressed cells; this translational repression function is independent of p97.\",\n      \"method\": \"KO cell lines, quantitative proteomics, UPR reporter assays, translation assays, epistasis with p97 inhibition\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with quantitative proteomics plus functional UPR/translation assays plus p97-independent epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"38177917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The extended UBA domain of UBXN1 specifically recognizes K6-linked diubiquitin: a C-terminally extended form of the UBA domain confers K6-linkage specificity, converging the two solution conformations of K6 diUb into a single conformation upon binding; the non-extended UBA domain does not show linkage preference.\",\n      \"method\": \"NMR spectroscopy with 15N-labeled synthetic diubiquitins, chemical shift perturbation, structural analysis\",\n      \"journal\": \"Frontiers in chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural determination with domain-specific variant comparison, rigorous biophysical method with functional interpretation\",\n      \"pmids\": [\"32039147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UBA-UBX proteins p47 and SAKS1 (UBXN1) have opposing roles in ERAD substrate degradation: p47 promotes degradation of α-TCR while SAKS1 delays it; SAKS1 selectively inhibits degradation of ERAD substrates without affecting cytosolic proteasomal substrates; expression of SAKS1 is reduced in cells stably expressing ERAD substrates and elevated upon ER stress.\",\n      \"method\": \"ERAD substrate degradation assays (α-TCR, α1-antitrypsin, δCD3), siRNA knockdown, pulse-chase/cycloheximide chase, stable cell lines expressing ERAD substrates\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional degradation assay with KD, single lab, single method per substrate\",\n      \"pmids\": [\"27785701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBXN1 promotes noncanonical inflammasome activation: together with unanchored K48/K63-linked polyubiquitin chains, UBXN1 binds caspase-4/11, promoting their assembly and activation; UBXN1 deficiency impairs caspase-4/11 activation, cytokine secretion, and pyroptosis in response to intracellular LPS; UBXN1-deficient mice are protected from LPS- and CLP-induced sepsis.\",\n      \"method\": \"Co-immunoprecipitation (UBXN1–caspase-4/11 interaction), KO cell lines and mice, inflammasome activation assays, recombinant USP5 depletion of unanchored polyUb, USP5 inhibitor experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional in-cell and in-vivo readouts plus chemical perturbation; preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.10.30.621131\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBR5 mediates Lys11-linked polyubiquitination and degradation of UBXN1 downstream of SUB1/PC4, thereby activating NF-κB signaling; SUB1 interacts with UBR5 and increases its protein level, leading to reduced UBXN1 and consequently elevated NF-κB activity.\",\n      \"method\": \"Co-immunoprecipitation (SUB1–UBR5 interaction), ubiquitination assays (Lys11 linkage), KO/knockdown, NF-κB reporter assays, in vivo tumor models\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with ubiquitination linkage determination and functional downstream readout; single lab\",\n      \"pmids\": [\"38240906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF2 accelerates UBXN1 mRNA degradation via METTL3-mediated m6A modification, leading to reduced UBXN1 protein and consequent NF-κB activation; UBXN1 overexpression attenuates the oncogenic effect of YTHDF2 overexpression.\",\n      \"method\": \"RNA immunoprecipitation (RIP), methylated RIP (MeRIP), RNA stability assays, siRNA knockdown/overexpression, orthotopic xenograft models\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and MeRIP establish m6A-dependent binding, RNA stability assay confirms mRNA decay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34246306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The lncRNA PRADX recruits the PRC2/DDX5 complex to the UBXN1 gene promoter, increasing H3K27 trimethylation and suppressing UBXN1 transcription, which in turn promotes NF-κB activity.\",\n      \"method\": \"ChIRP (chromatin isolation by RNA purification), ChIP, Co-IP, siRNA knockdown, H3K27me3 ChIP at UBXN1 promoter, xenograft models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIRP and ChIP establish lncRNA–chromatin interaction at UBXN1 locus; functional downstream readout; single lab\",\n      \"pmids\": [\"33754075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBXN1 interacts with the inner mitochondrial membrane protein prohibitin (PHB) and sustains PHB expression; UBXN1 inhibition triggers mitochondrial damage and HCC cell apoptosis, indicating a role in maintaining mitochondrial homeostasis.\",\n      \"method\": \"Co-immunoprecipitation (UBXN1–PHB), KO/knockdown, apoptosis assays (TUNEL, FACS), mouse liver tumor models (Sleeping Beauty transposon)\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with in vivo phenotype, single lab, single binding method\",\n      \"pmids\": [\"38773518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UBXN1 interacts with the TGEV coronavirus S1 spike protein and positively supports viral replication; UBXN1 knockdown reduces viral titer and S1 expression while overexpression increases viral copy number; UBXN1 negatively regulates IFN-β expression after TGEV infection.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, Co-immunoprecipitation, siRNA knockdown, overexpression, viral titer assays\",\n      \"journal\": \"Veterinary research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — initial interaction identified by yeast two-hybrid and pulldown, functional data from single lab; porcine virus model with limited mechanistic depth\",\n      \"pmids\": [\"31029162\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBXN1 is a multifunctional UBA-UBX domain protein that acts as a VCP/p97 cofactor and ubiquitin reader: its UBA domain specifically recognizes K6-linked polyubiquitin (e.g., on autoubiquitinated BRCA1) to inhibit BRCA1/BARD1 E3 ligase activity, while its UBX domain engages p97 to mediate triage of ubiquitylated BAG6 clients, ERAD substrate selectivity, aggresome formation, and MFN2 removal from mitochondria during PRKN-dependent mitophagy; independently of p97, UBXN1 represses translation to maintain ER proteostasis, negatively regulates TNFα-triggered NF-κB signaling by competitively blocking cIAP1 recruitment to TNFR1 and inhibiting RIP1 polyubiquitination, suppresses RLR/MAVS-mediated antiviral interferon responses by disrupting the MAVS/TRAF3/TRAF6 signalosome, and promotes noncanonical inflammasome activation by binding caspase-4/11 together with unanchored K48/K63-linked polyubiquitin chains; UBXN1 expression is itself regulated at multiple levels including METTL3/YTHDF2-dependent m6A mRNA decay, PRC2-mediated H3K27 methylation at its promoter, and UBR5-mediated Lys11-linked ubiquitination and degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBXN1 is a UBA-UBX domain protein that functions both as a VCP/p97 cofactor and as a linkage-selective ubiquitin reader controlling protein quality control and innate immune signaling [#3, #1]. Its extended UBA domain confers specificity for K6-linked polyubiquitin, collapsing the two solution conformations of K6 diubiquitin into a single bound conformation [#8]; through this activity UBXN1 recognizes autoubiquitinated BRCA1 and, via additional ubiquitin-independent contacts to the BRCA1/BARD1 heterodimer, sharply represses its E3 ligase activity [#1]. As a p97 adaptor it requires both polyubiquitin binding (UBA) and p97 binding (UBX), and couples ubiquitin recognition to triage of clients: it negatively modulates ERAD by protecting polyubiquitin chains from deubiquitinases and delaying substrate degradation [#3, #9], directs the VCP-dependent disposal of ubiquitylated BAG6 clients prior to ER insertion [#4], is required for aggresome formation and clearance of polyQ inclusions [#6], and translocates with VCP to depolarized mitochondria during PRKN-dependent mitophagy to facilitate MFN2 removal [#5]. Independently of p97, UBXN1 represses translation to restrain the unfolded protein response and maintain ER proteostasis [#7]. UBXN1 also acts as a negative regulator of inflammatory and antiviral signaling: it blocks cIAP1 recruitment to TNFR1 to limit RIP1 polyubiquitination and NF-\\u03baB activation [#2], and binds MAVS to disrupt the MAVS/TRAF3/TRAF6 signalosome and dampen RNA-virus-induced interferon responses [#0]. Consistent with its role as a signaling brake, UBXN1 abundance is suppressed at multiple levels\\u2014METTL3/YTHDF2-dependent m6A mRNA decay [#12], PRC2-mediated H3K27 trimethylation at its promoter [#13], and UBR5-mediated Lys11-linked ubiquitination and degradation [#11]\\u2014each releasing NF-\\u03baB activity.\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established UBXN1 as a linkage-selective ubiquitin reader that suppresses an E3 ligase, defining a non-degradative function for its UBA domain.\",\n      \"evidence\": \"Biochemical pulldown, in vitro ubiquitination, and domain mapping showing UBA binding to K6-polyUb on BRCA1 plus ubiquitin-independent BRCA1/BARD1 contacts that reduce ligase activity\",\n      \"pmids\": [\"20351172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequences for BRCA1-dependent DNA repair not established\", \"Stoichiometry of inhibition unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined UBXN1 as a bona fide p97 adaptor whose ubiquitin and p97 binding cooperate, and showed it negatively tunes ERAD by shielding chains from deubiquitination.\",\n      \"evidence\": \"In vitro p97 binding assays, ERAD substrate degradation assays, and deubiquitinase (ataxin-3) protection assays\",\n      \"pmids\": [\"21135095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which ERAD substrates are physiologically affected not defined\", \"Mechanism of chain protection structurally unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed UBXN1 acts as a virus-induced brake on RLR/MAVS antiviral signaling, distinguishing RNA-virus-specific suppression from TLR/DNA-virus pathways.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA/overexpression, and IFN reporter assays across multiple RNA viruses\",\n      \"pmids\": [\"23545497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ubiquitin-binding or p97 is required for MAVS regulation not addressed\", \"In vivo antiviral relevance untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a p97-independent role for UBXN1 in restraining NF-\\u03baB by competitively blocking cIAP1 recruitment to TNFR1.\",\n      \"evidence\": \"siRNA screen, competitive Co-IP, RIP1 ubiquitination and NF-\\u03baB reporter assays, with VCP knockdown ruling out p97 dependence\",\n      \"pmids\": [\"25681446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cIAP1 competition unknown\", \"Whether ubiquitin binding contributes not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Distinguished UBXN1 from other UBA-UBX proteins functionally, showing it selectively delays ERAD substrate degradation and is stress-regulated.\",\n      \"evidence\": \"ERAD substrate degradation assays with multiple substrates and siRNA knockdown comparing p47 and SAKS1\",\n      \"pmids\": [\"27785701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method per substrate\", \"Mechanistic basis for substrate selectivity not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed UBXN1 in the BAG6 triage pathway as the VCP adaptor handling ubiquitylated cytosolic clients before ER insertion, distinct from ERAD.\",\n      \"evidence\": \"Reciprocal Co-IP, KO cell lines, degradation assays, and solubility fractionation with proteotoxic stress assays\",\n      \"pmids\": [\"29685906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Client repertoire incompletely mapped\", \"How triage versus ERAD is discriminated unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the structural basis for K6-linkage selectivity, showing a C-terminally extended UBA domain enforces specificity.\",\n      \"evidence\": \"NMR with 15N-labeled synthetic diubiquitins comparing extended versus non-extended UBA constructs\",\n      \"pmids\": [\"32039147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length protein conformation not solved\", \"Cellular K6-chain ligands beyond BRCA1 not catalogued\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended UBXN1's quality-control role to organelle clearance, defining it as a VCP cofactor for aggresome formation and for PRKN-dependent mitophagy.\",\n      \"evidence\": \"KO cell lines, imaging, C. elegans HD model, mitochondrial fractionation, UBX-domain-dependent PRKN Co-IP, and mitophagy flux assays\",\n      \"pmids\": [\"33712450\", \"33966597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitin substrates at aggresomes/mitochondria not all defined\", \"Relationship between aggresome and mitophagy functions unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed UBXN1 is a transcriptionally and post-transcriptionally suppressed NF-\\u03baB brake, via m6A-driven mRNA decay and PRC2-mediated promoter silencing.\",\n      \"evidence\": \"MeRIP/RIP and RNA stability assays (METTL3/YTHDF2); ChIRP/ChIP at the UBXN1 promoter (PRADX/PRC2/DDX5); NF-\\u03baB reporters and xenografts\",\n      \"pmids\": [\"34246306\", \"33754075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effect on NF-\\u03baB independent of confounding pathways not fully isolated\", \"Tissue specificity of regulation unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified UBR5 as an E3 that degrades UBXN1 via Lys11-linked ubiquitination downstream of SUB1, closing a regulatory loop releasing NF-\\u03baB.\",\n      \"evidence\": \"Co-IP, Lys11-linkage ubiquitination assays, knockdown, NF-\\u03baB reporters, and in vivo tumor models\",\n      \"pmids\": [\"38240906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"UBR5 degron on UBXN1 not mapped\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a p97-independent role for UBXN1 in repressing translation to restrain the UPR and maintain ER proteostasis.\",\n      \"evidence\": \"KO cells with quantitative proteomics, UPR reporters, translation assays, and p97-inhibition epistasis\",\n      \"pmids\": [\"38177917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of translational repression unknown\", \"Direct effectors of translation control unidentified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated UBXN1 as a positive regulator of noncanonical inflammasome activation through caspase-4/11 binding with unanchored polyubiquitin.\",\n      \"evidence\": \"Co-IP, KO cells and mice, inflammasome/pyroptosis assays, and USP5-based depletion of unanchored polyUb (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.10.30.621131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"How a negative NF-\\u03baB regulator positively drives inflammasomes mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked UBXN1 to mitochondrial homeostasis through interaction with prohibitin and support of HCC cell survival.\",\n      \"evidence\": \"Co-IP, KO/knockdown, apoptosis assays, and Sleeping Beauty mouse liver tumor models\",\n      \"pmids\": [\"38773518\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single binding method\", \"Mechanism by which UBXN1 sustains PHB expression unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UBXN1 integrates its dual identity\\u2014p97-coupled quality-control adaptor versus p97-independent signaling/translation regulator\\u2014into a coherent regulatory logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking ubiquitin-linkage selectivity to specific cellular outputs\", \"Determinants of when UBXN1 engages p97 versus acts independently unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 0, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 7, 9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 4, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 0]}\n    ],\n    \"complexes\": [\"VCP/p97-UBXN1 complex\", \"BAG6 complex\"],\n    \"partners\": [\"VCP\", \"BRCA1\", \"BARD1\", \"MAVS\", \"BIRC2\", \"PRKN\", \"BAG6\", \"PHB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}