{"gene":"UBXN2B","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2013,"finding":"UBXN-2 (C. elegans ortholog of human p37/UBXN2B), a substrate adaptor of the AAA ATPase CDC-48/p97, is required to coordinate centrosome maturation timing with mitosis. UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 (Aurora A), and UBXN-2 depletion caused excess Aurora A recruitment to centrosomes and premature centrosome maturation. Co-depletion of AIR-1 partially rescued the spindle alignment defect. In human cells, depletion of p37/p47 (UBXN2B orthologs) caused Aurora A accumulation at centrosomes and a delay in centrosome separation that was rescued by Aurora A inhibition.","method":"RNAi depletion in C. elegans embryos and human cells, coimmunoprecipitation, genetic epistasis (double depletion rescue)","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal CoIP plus genetic epistasis plus functional phenotypic rescue in two organisms","pmids":["23649807"],"is_preprint":false},{"year":2017,"finding":"p37/UBXN2B, a cofactor of the p97 AAA ATPase, regulates spindle orientation in mammalian cells by limiting cortical NuMA levels. p37 acts through the phosphatase PP1 and its regulatory subunit Repo-Man to control NuMA cortical accumulation, independently of Gαi, Aurora A, and PP2A. In anaphase, PP1/Repo-Man promotes NuMA cortical accumulation; in metaphase, p37 negatively regulates this PP1 function to maintain correct spindle orientation.","method":"siRNA knockdown in mammalian cells, epistasis analysis with PP1/Repo-Man, Aurora A inhibition, Gαi depletion; immunofluorescence quantification of cortical NuMA","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO/KD with defined cellular phenotype plus multi-step epistasis placing p37 in pathway relative to PP1/Repo-Man","pmids":["29222185"],"is_preprint":false},{"year":2024,"finding":"p37/UBXN2B is a major regulator of VCP/p97 nucleocytoplasmic shuttling. p37-dependent VCP localization is required for cytosolic VCP functions (autophagy) and nuclear VCP functions (DNA damage repair). Disease-causing VCP mutations (multisystem proteinopathy) enhance VCP–p37 association, reducing nuclear VCP and increasing DNA damage susceptibility; lowering p37 levels normalized VCP nuclear localization and DNA damage susceptibility in mutant cells.","method":"siRNA knockdown, overexpression, subcellular fractionation, co-immunoprecipitation, DNA damage assays, autophagy flux assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (fractionation, CoIP, functional rescue) demonstrating mechanism in single rigorous study","pmids":["38701207"],"is_preprint":false},{"year":2006,"finding":"p37 (UBXN2B) forms a complex with p97 in the cytosol and is required for Golgi and ER biogenesis during interphase and reassembly at the end of mitosis. In an in vitro Golgi reassembly assay, the p97/p37 complex has membrane fusion activity. This pathway requires p115-GM130 tethering and SNARE GS15, but not syntaxin5. VCIP135 is required but its deubiquitinating activity is dispensable for p97/p37-mediated activities.","method":"siRNA knockdown, anti-p37 antibody microinjection, in vitro Golgi reassembly assay, complex purification","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro membrane fusion reconstitution plus siRNA epistasis plus pathway component dissection","pmids":["17141156"],"is_preprint":false},{"year":2010,"finding":"p37 (UBXN2B) is phosphorylated on Serine-56 and Threonine-59 by Cdc2 at mitosis. Phosphorylated p37 does not bind to Golgi membranes. Phosphomimetic mutant p37(S56D,T59D) fails to cause cisternal regrowth in an in vitro Golgi reassembly assay, demonstrating that Cdc2-mediated phosphorylation of p37 inhibits the p97/p37 membrane fusion pathway and contributes to Golgi disassembly at mitosis.","method":"Site-directed mutagenesis, in vitro Golgi reassembly assay, Golgi membrane binding assay, phosphorylation mapping","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with phosphomimetic mutagenesis establishing Cdc2 as writer and functional consequence","pmids":["20875789"],"is_preprint":false},{"year":2022,"finding":"Molecular docking and molecular dynamics simulations defined the interaction between the UBX domain of human p37 (UBXN2B) and the N-D1 domain of p97 at atomic resolution. Key hydrophobic contacts and two hydrogen bonds were identified; residues in the p37 UBX domain involved in binding to the p97 N-D1 interface are highly conserved among UBX cofactors.","method":"Homology modeling, molecular docking (HDOCK, HAWKDOCK), MM-GBSA binding free energy calculations, molecular dynamics simulation","journal":"BMC molecular and cell biology","confidence":"Low","confidence_rationale":"Tier 4 — computational prediction only, no experimental validation of interaction residues","pmids":["36088301"],"is_preprint":false},{"year":2016,"finding":"Screening of p97 inhibitor analogues revealed that the cofactor p37 (UBXN2B), unlike p47, does not significantly alter the potency of most ATP-competitive p97 inhibitors, highlighting functional differences between p37 and p47 in influencing p97 conformation and inhibitor sensitivity.","method":"ATPase activity assay with p97-p37 and p97-Npl4-Ufd1 complexes, inhibitor screening of 200 analogues","journal":"ChemMedChem","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro ATPase assay with reconstituted p97-p37 complex; single study","pmids":["27043824"],"is_preprint":false}],"current_model":"UBXN2B (p37) is a substrate adaptor/cofactor of the AAA ATPase p97/VCP that (1) forms a p97/p37 complex with membrane fusion activity required for Golgi and ER biogenesis in interphase and at mitotic exit, (2) is inhibited at mitosis when Cdc2 phosphorylates p37 on Ser56/Thr59 to block Golgi membrane binding and drive organelle disassembly, (3) limits centrosomal Aurora A recruitment via CDC-48/p97 to coordinate centrosome maturation with mitosis, (4) regulates spindle orientation by restricting cortical NuMA levels through negative regulation of the PP1/Repo-Man phosphatase, and (5) controls p97 nucleocytoplasmic distribution, which is required for both cytosolic autophagy and nuclear DNA damage repair functions of p97."},"narrative":{"teleology":[{"year":2006,"claim":"Identifying p37 as a p97 cofactor with membrane fusion activity resolved how Golgi and ER biogenesis are driven post-mitotically and during interphase, establishing a p97/p37-specific pathway distinct from the known p97/p47 route.","evidence":"In vitro Golgi reassembly assay, siRNA knockdown, antibody microinjection, pathway component epistasis in mammalian cells","pmids":["17141156"],"confidence":"High","gaps":["Structural basis of p37 membrane recruitment is undefined","Whether p97/p37 directly drives ER tubule fusion or acts indirectly is unresolved","Relative contributions of p97/p37 vs p97/p47 to post-mitotic Golgi reassembly in vivo are unclear"]},{"year":2010,"claim":"Demonstrating that Cdc2 phosphorylation of p37 on Ser56/Thr59 blocks Golgi membrane binding and membrane fusion activity explained how mitotic kinase signaling inactivates the p97/p37 pathway to promote Golgi disassembly at mitotic entry.","evidence":"Phosphomimetic mutagenesis (S56D/T59D), in vitro Golgi reassembly and membrane-binding assays, phosphorylation site mapping","pmids":["20875789"],"confidence":"High","gaps":["Whether additional kinases phosphorylate p37 at mitosis is unknown","The phosphatase responsible for p37 dephosphorylation at mitotic exit is unidentified","In vivo validation of phospho-site mutant phenotypes has not been reported"]},{"year":2013,"claim":"Showing that UBXN-2/p37 limits centrosomal Aurora A recruitment via CDC-48/p97 extended p37 function beyond membrane dynamics to mitotic spindle regulation and centrosome maturation timing.","evidence":"RNAi in C. elegans embryos and human cells, coimmunoprecipitation with Aurora A, genetic epistasis (double depletion rescue), Aurora A inhibitor rescue","pmids":["23649807"],"confidence":"High","gaps":["Whether p37/p97 directly ubiquitin-dependently extracts Aurora A from centrosomes is unresolved","The substrate(s) of p97/p37 at centrosomes have not been identified","Whether p37 and p47 are redundant in centrosome regulation remains unclear"]},{"year":2017,"claim":"Establishing that p37 restricts cortical NuMA levels through negative regulation of PP1/Repo-Man, independently of Gαi and Aurora A, defined a second mitotic spindle-orientation pathway controlled by p37.","evidence":"siRNA knockdown in mammalian cells, multi-step epistasis with PP1/Repo-Man, Aurora A inhibition, Gαi depletion, immunofluorescence quantification","pmids":["29222185"],"confidence":"High","gaps":["Whether p37/p97 directly binds or extracts Repo-Man is unknown","The ubiquitin signal (if any) linking p97/p37 to PP1/Repo-Man regulation is uncharacterized","How p37-mediated NuMA restriction is relieved at anaphase is not established"]},{"year":2024,"claim":"Demonstrating that p37 controls p97 nucleocytoplasmic distribution — required for both cytosolic autophagy and nuclear DNA damage repair — connected p37 to disease-relevant VCP pathology, as multisystem proteinopathy VCP mutations enhance VCP–p37 association and reduce nuclear VCP.","evidence":"siRNA knockdown, overexpression, subcellular fractionation, co-immunoprecipitation, DNA damage and autophagy flux assays in mammalian cells","pmids":["38701207"],"confidence":"High","gaps":["The mechanism by which p37 controls p97 nuclear import or export is not defined","Whether p37 levels are altered in patient tissues with VCP mutations is unknown","Contribution of other p97 cofactors to nucleocytoplasmic shuttling has not been systematically compared"]},{"year":null,"claim":"The direct mechanism by which p37 controls p97 nucleocytoplasmic shuttling, the identity of p97/p37 substrates at centrosomes and the cortex, and the structural basis of p37 membrane recognition remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No experimentally validated atomic structure of the p97–p37 complex exists","Substrates extracted by p97/p37 at centrosomes and at the cell cortex are unidentified","The nuclear import/export signal or carrier mediating p37-dependent p97 shuttling is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,3]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2]}],"complexes":["p97/p37 complex"],"partners":["VCP","AURKA","CDCA2","NUMA1","VCIP135"],"other_free_text":[]},"mechanistic_narrative":"UBXN2B (p37) is a UBX-domain-containing substrate adaptor/cofactor of the AAA ATPase p97/VCP that coordinates organelle biogenesis, mitotic progression, and p97 subcellular distribution. The p97/p37 complex possesses membrane fusion activity required for Golgi and ER biogenesis during interphase and organelle reassembly at mitotic exit, a function inhibited when Cdc2 phosphorylates p37 on Ser56/Thr59 to block Golgi membrane binding and drive mitotic Golgi disassembly [PMID:17141156, PMID:20875789]. UBXN2B limits centrosomal Aurora A recruitment through CDC-48/p97 to coordinate centrosome maturation timing and regulates spindle orientation by restricting cortical NuMA levels via negative regulation of PP1/Repo-Man [PMID:23649807, PMID:29222185]. UBXN2B also controls p97 nucleocytoplasmic shuttling, which is required for both cytosolic autophagy and nuclear DNA damage repair; disease-causing VCP mutations enhance VCP–p37 association, reducing nuclear VCP and increasing DNA damage susceptibility [PMID:38701207]."},"prefetch_data":{"uniprot":{"accession":"Q14CS0","full_name":"UBX domain-containing protein 2B","aliases":["NSFL1 cofactor p37","p97 cofactor p37"],"length_aa":331,"mass_kda":37.1,"function":"Adapter protein required for Golgi and endoplasmic reticulum biogenesis (PubMed:17141156). Involved in Golgi and endoplasmic reticulum maintenance during interphase and in their reassembly at the end of mitosis (PubMed:17141156). The complex formed with VCP has membrane fusion activity; membrane fusion activity requires USO1-GOLGA2 tethering and BET1L (PubMed:17141156). VCPIP1 is also required, but not its deubiquitinating activity (PubMed:17141156). Together with NSFL1C/p47, regulates the centrosomal levels of kinase AURKA/Aurora A during mitotic progression by promoting AURKA removal from centrosomes in prophase (PubMed:23649807). Also, regulates spindle orientation during mitosis (PubMed:23649807)","subcellular_location":"Nucleus; Cytoplasm, cytosol; Endoplasmic reticulum; Golgi apparatus; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q14CS0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBXN2B","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":[{"gene":"VCP","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/UBXN2B","total_profiled":1310},"omim":[{"mim_id":"621109","title":"VCP NUCLEAR COFACTOR FAMILY, MEMBER 1; VCF1","url":"https://www.omim.org/entry/621109"},{"mim_id":"610686","title":"UBX DOMAIN PROTEIN 2B; UBXN2B","url":"https://www.omim.org/entry/610686"},{"mim_id":"601023","title":"VALOSIN-CONTAINING PROTEIN; VCP","url":"https://www.omim.org/entry/601023"},{"mim_id":"301141","title":"VCP NUCLEAR COFACTOR FAMILY, MEMBER 2; VCF2","url":"https://www.omim.org/entry/301141"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UBXN2B"},"hgnc":{"alias_symbol":["p37"],"prev_symbol":[]},"alphafold":{"accession":"Q14CS0","domains":[{"cath_id":"3.30.420.210","chopping":"79-98_138-208","consensus_level":"medium","plddt":81.5919,"start":79,"end":208},{"cath_id":"3.10.20.90","chopping":"255-329","consensus_level":"high","plddt":84.0803,"start":255,"end":329}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14CS0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14CS0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14CS0-F1-predicted_aligned_error_v6.png","plddt_mean":70.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBXN2B","jax_strain_url":"https://www.jax.org/strain/search?query=UBXN2B"},"sequence":{"accession":"Q14CS0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14CS0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14CS0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14CS0"}},"corpus_meta":[{"pmid":"9175831","id":"PMC_9175831","title":"Borrelia burgdorferi P35 and P37 proteins, expressed in vivo, elicit protective immunity.","date":"1997","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/9175831","citation_count":123,"is_preprint":false},{"pmid":"12944492","id":"PMC_12944492","title":"Selective degradation of AU-rich mRNAs promoted by the p37 AUF1 protein isoform.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12944492","citation_count":119,"is_preprint":false},{"pmid":"17141156","id":"PMC_17141156","title":"p37 is a p97 adaptor required for Golgi and ER biogenesis in interphase and at the end of mitosis.","date":"2006","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/17141156","citation_count":88,"is_preprint":false},{"pmid":"9228079","id":"PMC_9228079","title":"A complex consisting of human replication factor C p40, p37, and p36 subunits is a DNA-dependent ATPase and an intermediate in the assembly of the holoenzyme.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9228079","citation_count":69,"is_preprint":false},{"pmid":"18347140","id":"PMC_18347140","title":"p37 from Mycoplasma hyorhinis promotes cancer cell invasiveness and metastasis through activation of MMP-2 and followed by phosphorylation of EGFR.","date":"2008","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/18347140","citation_count":65,"is_preprint":false},{"pmid":"8288647","id":"PMC_8288647","title":"Purified yeast RNA polymerase II reads through intrinsic blocks to elongation in response to the yeast TFIIS analogue, P37.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8288647","citation_count":55,"is_preprint":false},{"pmid":"19400954","id":"PMC_19400954","title":"Vaccinia virus p37 interacts with host proteins associated with LE-derived transport vesicle biogenesis.","date":"2009","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/19400954","citation_count":54,"is_preprint":false},{"pmid":"16020660","id":"PMC_16020660","title":"p37 Induces tumor invasiveness.","date":"2005","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/16020660","citation_count":52,"is_preprint":false},{"pmid":"9405398","id":"PMC_9405398","title":"Lipase activities of p37, the major envelope protein of vaccinia virus.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9405398","citation_count":51,"is_preprint":false},{"pmid":"15364940","id":"PMC_15364940","title":"The role of thiol species in the hypertolerance of Aspergillus sp. 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microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/9986810","citation_count":23,"is_preprint":false},{"pmid":"23649807","id":"PMC_23649807","title":"The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.","date":"2013","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23649807","citation_count":22,"is_preprint":false},{"pmid":"17580096","id":"PMC_17580096","title":"African swine fever virus p37 structural protein is localized in nuclear foci containing the viral DNA at early post-infection times.","date":"2007","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/17580096","citation_count":21,"is_preprint":false},{"pmid":"16415017","id":"PMC_16415017","title":"Nuclear export of African swine fever virus p37 protein occurs through two distinct pathways and is mediated by three independent signals.","date":"2006","source":"Journal of 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macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38458287","citation_count":4,"is_preprint":false},{"pmid":"37221882","id":"PMC_37221882","title":"Machine learning and classical MD simulation to identify inhibitors against the P37 envelope protein of monkeypox virus.","date":"2023","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/37221882","citation_count":4,"is_preprint":false},{"pmid":"32113194","id":"PMC_32113194","title":"Pantoea sp. P37 as a novel nonpathogenic host for the heterologous production of rhamnolipids.","date":"2020","source":"MicrobiologyOpen","url":"https://pubmed.ncbi.nlm.nih.gov/32113194","citation_count":4,"is_preprint":false},{"pmid":"12454480","id":"PMC_12454480","title":"Crystallization and preliminary X-ray analysis of the tumor metastasis factor p37.","date":"2002","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/12454480","citation_count":4,"is_preprint":false},{"pmid":"36051767","id":"PMC_36051767","title":"P25 and P37 proteins encoded by firespike leafroll-associated virus are viral suppressors of RNA silencing.","date":"2022","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36051767","citation_count":3,"is_preprint":false},{"pmid":"28036384","id":"PMC_28036384","title":"Mapping of a Mycoplasma-Neutralizing Epitope on the Mycoplasmal p37 Protein.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28036384","citation_count":3,"is_preprint":false},{"pmid":"31347183","id":"PMC_31347183","title":"Characterization of SE-P3, P16, P37, and P47 bacteriophages infecting Salmonella Enteritidis.","date":"2019","source":"Journal of basic microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31347183","citation_count":3,"is_preprint":false},{"pmid":"20440535","id":"PMC_20440535","title":"Transient metabolic modeling of Escherichia coli MG1655 and MG1655 DeltaackA-pta, DeltapoxB Deltapppc ppc-p37 for recombinant beta-galactosidase production.","date":"2010","source":"Journal of industrial microbiology & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/20440535","citation_count":3,"is_preprint":false},{"pmid":"29938600","id":"PMC_29938600","title":"A p37-based ELISA used to monitor anti- Mycoplasma hyorhinis IgG in serum from pigs immunized with inactivated M. hyorhinis vaccines.","date":"2018","source":"Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/29938600","citation_count":3,"is_preprint":false},{"pmid":"8968909","id":"PMC_8968909","title":"Detection of Antibodies to Pasteurella multocida by capture enzyme immunoassay using a monoclonal antibody against P37 antigen.","date":"1997","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/8968909","citation_count":2,"is_preprint":false},{"pmid":"16793666","id":"PMC_16793666","title":"Inhibition of the intimal hyperplasia in an arterial autograft model by blockade of the N-terminal of the integrin beta3 subunit by monoclonal antibody P37.","date":"1997","source":"Platelets","url":"https://pubmed.ncbi.nlm.nih.gov/16793666","citation_count":2,"is_preprint":false},{"pmid":"41256857","id":"PMC_41256857","title":"Immune tolerance induction using the thyrotropin receptor epitope 78-94 (p37) prevents Graves' disease in HLA-DR3 transgenic mice.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41256857","citation_count":1,"is_preprint":false},{"pmid":"31690259","id":"PMC_31690259","title":"Identification of specific B cell linear epitopes of mycoplasma hyorhinis P37 protein using monoclonal antibodies against baculovirus-expressed P37 protein.","date":"2019","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31690259","citation_count":1,"is_preprint":false},{"pmid":"28196145","id":"PMC_28196145","title":"Correction: Mapping of a Mycoplasma-Neutralizing Epitope on the Mycoplasmal p37 Protein.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28196145","citation_count":1,"is_preprint":false},{"pmid":"16378104","id":"PMC_16378104","title":"[Establishment of a stable and regulable 293 cell line expressing mycoplasma hyorhinis protein P37].","date":"2005","source":"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/16378104","citation_count":1,"is_preprint":false},{"pmid":"39393175","id":"PMC_39393175","title":"Phylogeography of Y-chromosome haplogroup I-P37.2 in Serbian population groups originating from distinct parts of the Balkan Peninsula.","date":"2024","source":"Forensic science international. 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UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 (Aurora A), and UBXN-2 depletion caused excess Aurora A recruitment to centrosomes and premature centrosome maturation. Co-depletion of AIR-1 partially rescued the spindle alignment defect. In human cells, depletion of p37/p47 (UBXN2B orthologs) caused Aurora A accumulation at centrosomes and a delay in centrosome separation that was rescued by Aurora A inhibition.\",\n      \"method\": \"RNAi depletion in C. elegans embryos and human cells, coimmunoprecipitation, genetic epistasis (double depletion rescue)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal CoIP plus genetic epistasis plus functional phenotypic rescue in two organisms\",\n      \"pmids\": [\"23649807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p37/UBXN2B, a cofactor of the p97 AAA ATPase, regulates spindle orientation in mammalian cells by limiting cortical NuMA levels. p37 acts through the phosphatase PP1 and its regulatory subunit Repo-Man to control NuMA cortical accumulation, independently of Gαi, Aurora A, and PP2A. In anaphase, PP1/Repo-Man promotes NuMA cortical accumulation; in metaphase, p37 negatively regulates this PP1 function to maintain correct spindle orientation.\",\n      \"method\": \"siRNA knockdown in mammalian cells, epistasis analysis with PP1/Repo-Man, Aurora A inhibition, Gαi depletion; immunofluorescence quantification of cortical NuMA\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/KD with defined cellular phenotype plus multi-step epistasis placing p37 in pathway relative to PP1/Repo-Man\",\n      \"pmids\": [\"29222185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"p37/UBXN2B is a major regulator of VCP/p97 nucleocytoplasmic shuttling. p37-dependent VCP localization is required for cytosolic VCP functions (autophagy) and nuclear VCP functions (DNA damage repair). Disease-causing VCP mutations (multisystem proteinopathy) enhance VCP–p37 association, reducing nuclear VCP and increasing DNA damage susceptibility; lowering p37 levels normalized VCP nuclear localization and DNA damage susceptibility in mutant cells.\",\n      \"method\": \"siRNA knockdown, overexpression, subcellular fractionation, co-immunoprecipitation, DNA damage assays, autophagy flux assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (fractionation, CoIP, functional rescue) demonstrating mechanism in single rigorous study\",\n      \"pmids\": [\"38701207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"p37 (UBXN2B) forms a complex with p97 in the cytosol and is required for Golgi and ER biogenesis during interphase and reassembly at the end of mitosis. In an in vitro Golgi reassembly assay, the p97/p37 complex has membrane fusion activity. This pathway requires p115-GM130 tethering and SNARE GS15, but not syntaxin5. VCIP135 is required but its deubiquitinating activity is dispensable for p97/p37-mediated activities.\",\n      \"method\": \"siRNA knockdown, anti-p37 antibody microinjection, in vitro Golgi reassembly assay, complex purification\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro membrane fusion reconstitution plus siRNA epistasis plus pathway component dissection\",\n      \"pmids\": [\"17141156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p37 (UBXN2B) is phosphorylated on Serine-56 and Threonine-59 by Cdc2 at mitosis. Phosphorylated p37 does not bind to Golgi membranes. Phosphomimetic mutant p37(S56D,T59D) fails to cause cisternal regrowth in an in vitro Golgi reassembly assay, demonstrating that Cdc2-mediated phosphorylation of p37 inhibits the p97/p37 membrane fusion pathway and contributes to Golgi disassembly at mitosis.\",\n      \"method\": \"Site-directed mutagenesis, in vitro Golgi reassembly assay, Golgi membrane binding assay, phosphorylation mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with phosphomimetic mutagenesis establishing Cdc2 as writer and functional consequence\",\n      \"pmids\": [\"20875789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Molecular docking and molecular dynamics simulations defined the interaction between the UBX domain of human p37 (UBXN2B) and the N-D1 domain of p97 at atomic resolution. Key hydrophobic contacts and two hydrogen bonds were identified; residues in the p37 UBX domain involved in binding to the p97 N-D1 interface are highly conserved among UBX cofactors.\",\n      \"method\": \"Homology modeling, molecular docking (HDOCK, HAWKDOCK), MM-GBSA binding free energy calculations, molecular dynamics simulation\",\n      \"journal\": \"BMC molecular and cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction only, no experimental validation of interaction residues\",\n      \"pmids\": [\"36088301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Screening of p97 inhibitor analogues revealed that the cofactor p37 (UBXN2B), unlike p47, does not significantly alter the potency of most ATP-competitive p97 inhibitors, highlighting functional differences between p37 and p47 in influencing p97 conformation and inhibitor sensitivity.\",\n      \"method\": \"ATPase activity assay with p97-p37 and p97-Npl4-Ufd1 complexes, inhibitor screening of 200 analogues\",\n      \"journal\": \"ChemMedChem\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro ATPase assay with reconstituted p97-p37 complex; single study\",\n      \"pmids\": [\"27043824\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBXN2B (p37) is a substrate adaptor/cofactor of the AAA ATPase p97/VCP that (1) forms a p97/p37 complex with membrane fusion activity required for Golgi and ER biogenesis in interphase and at mitotic exit, (2) is inhibited at mitosis when Cdc2 phosphorylates p37 on Ser56/Thr59 to block Golgi membrane binding and drive organelle disassembly, (3) limits centrosomal Aurora A recruitment via CDC-48/p97 to coordinate centrosome maturation with mitosis, (4) regulates spindle orientation by restricting cortical NuMA levels through negative regulation of the PP1/Repo-Man phosphatase, and (5) controls p97 nucleocytoplasmic distribution, which is required for both cytosolic autophagy and nuclear DNA damage repair functions of p97.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"UBXN2B (p37) is a UBX-domain-containing substrate adaptor/cofactor of the AAA ATPase p97/VCP that coordinates organelle biogenesis, mitotic progression, and p97 subcellular distribution. The p97/p37 complex possesses membrane fusion activity required for Golgi and ER biogenesis during interphase and organelle reassembly at mitotic exit, a function inhibited when Cdc2 phosphorylates p37 on Ser56/Thr59 to block Golgi membrane binding and drive mitotic Golgi disassembly [PMID:17141156, PMID:20875789]. UBXN2B limits centrosomal Aurora A recruitment through CDC-48/p97 to coordinate centrosome maturation timing and regulates spindle orientation by restricting cortical NuMA levels via negative regulation of PP1/Repo-Man [PMID:23649807, PMID:29222185]. UBXN2B also controls p97 nucleocytoplasmic shuttling, which is required for both cytosolic autophagy and nuclear DNA damage repair; disease-causing VCP mutations enhance VCP–p37 association, reducing nuclear VCP and increasing DNA damage susceptibility [PMID:38701207].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying p37 as a p97 cofactor with membrane fusion activity resolved how Golgi and ER biogenesis are driven post-mitotically and during interphase, establishing a p97/p37-specific pathway distinct from the known p97/p47 route.\",\n      \"evidence\": \"In vitro Golgi reassembly assay, siRNA knockdown, antibody microinjection, pathway component epistasis in mammalian cells\",\n      \"pmids\": [\"17141156\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of p37 membrane recruitment is undefined\",\n        \"Whether p97/p37 directly drives ER tubule fusion or acts indirectly is unresolved\",\n        \"Relative contributions of p97/p37 vs p97/p47 to post-mitotic Golgi reassembly in vivo are unclear\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that Cdc2 phosphorylation of p37 on Ser56/Thr59 blocks Golgi membrane binding and membrane fusion activity explained how mitotic kinase signaling inactivates the p97/p37 pathway to promote Golgi disassembly at mitotic entry.\",\n      \"evidence\": \"Phosphomimetic mutagenesis (S56D/T59D), in vitro Golgi reassembly and membrane-binding assays, phosphorylation site mapping\",\n      \"pmids\": [\"20875789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether additional kinases phosphorylate p37 at mitosis is unknown\",\n        \"The phosphatase responsible for p37 dephosphorylation at mitotic exit is unidentified\",\n        \"In vivo validation of phospho-site mutant phenotypes has not been reported\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that UBXN-2/p37 limits centrosomal Aurora A recruitment via CDC-48/p97 extended p37 function beyond membrane dynamics to mitotic spindle regulation and centrosome maturation timing.\",\n      \"evidence\": \"RNAi in C. elegans embryos and human cells, coimmunoprecipitation with Aurora A, genetic epistasis (double depletion rescue), Aurora A inhibitor rescue\",\n      \"pmids\": [\"23649807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether p37/p97 directly ubiquitin-dependently extracts Aurora A from centrosomes is unresolved\",\n        \"The substrate(s) of p97/p37 at centrosomes have not been identified\",\n        \"Whether p37 and p47 are redundant in centrosome regulation remains unclear\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Establishing that p37 restricts cortical NuMA levels through negative regulation of PP1/Repo-Man, independently of Gαi and Aurora A, defined a second mitotic spindle-orientation pathway controlled by p37.\",\n      \"evidence\": \"siRNA knockdown in mammalian cells, multi-step epistasis with PP1/Repo-Man, Aurora A inhibition, Gαi depletion, immunofluorescence quantification\",\n      \"pmids\": [\"29222185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether p37/p97 directly binds or extracts Repo-Man is unknown\",\n        \"The ubiquitin signal (if any) linking p97/p37 to PP1/Repo-Man regulation is uncharacterized\",\n        \"How p37-mediated NuMA restriction is relieved at anaphase is not established\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that p37 controls p97 nucleocytoplasmic distribution — required for both cytosolic autophagy and nuclear DNA damage repair — connected p37 to disease-relevant VCP pathology, as multisystem proteinopathy VCP mutations enhance VCP–p37 association and reduce nuclear VCP.\",\n      \"evidence\": \"siRNA knockdown, overexpression, subcellular fractionation, co-immunoprecipitation, DNA damage and autophagy flux assays in mammalian cells\",\n      \"pmids\": [\"38701207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The mechanism by which p37 controls p97 nuclear import or export is not defined\",\n        \"Whether p37 levels are altered in patient tissues with VCP mutations is unknown\",\n        \"Contribution of other p97 cofactors to nucleocytoplasmic shuttling has not been systematically compared\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct mechanism by which p37 controls p97 nucleocytoplasmic shuttling, the identity of p97/p37 substrates at centrosomes and the cortex, and the structural basis of p37 membrane recognition remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No experimentally validated atomic structure of the p97–p37 complex exists\",\n        \"Substrates extracted by p97/p37 at centrosomes and at the cell cortex are unidentified\",\n        \"The nuclear import/export signal or carrier mediating p37-dependent p97 shuttling is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"p97/p37 complex\"\n    ],\n    \"partners\": [\n      \"VCP\",\n      \"AURKA\",\n      \"CDCA2\",\n      \"NUMA1\",\n      \"VCIP135\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}