{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q7Z6Z7","secondaryAccessions":["O15029","Q4G2Z2","Q5H961","Q6P4D0","Q8NG67","Q9BUI0","Q9HCJ4","Q9NSL6","Q9P0A9"],"uniProtkbId":"HUWE1_HUMAN","entryAudit":{"firstPublicDate":"2004-07-19","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2005-08-30","entryVersion":216,"sequenceVersion":3},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"value":"E3 ubiquitin-protein ligase HUWE1"},"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15989957"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19713937"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26214738"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30217973"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35776542"}],"value":"2.3.2.26"}]},"alternativeNames":[{"fullName":{"value":"ARF-binding protein 1"},"shortNames":[{"value":"ARF-BP1"}]},{"fullName":{"value":"HECT, UBA and WWE domain-containing protein 1"}},{"fullName":{"value":"HECT-type E3 ubiquitin transferase HUWE1"}},{"fullName":{"value":"Homologous to E6AP carboxyl terminus homologous protein 9"},"shortNames":[{"value":"HectH9"}]},{"fullName":{"value":"Large structure of UREB1"},"shortNames":[{"value":"LASU1"}]},{"fullName":{"value":"Mcl-1 ubiquitin ligase E3"},"shortNames":[{"value":"Mule"}]},{"fullName":{"value":"Upstream regulatory element-binding protein 1"},"shortNames":[{"value":"URE-B1"},{"value":"URE-binding protein 1"}]}]},"genes":[{"geneName":{"value":"HUWE1"},"synonyms":[{"value":"KIAA0312"},{"value":"KIAA1578"},{"value":"UREB1"}],"orfNames":[{"value":"HSPC272"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P51593"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q7TMY8"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15567145"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15767685"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15989956"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15989957"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17567951"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18488021"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19037095"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19713937"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20534529"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26214738"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"27746020"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30217973"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35776542"}],"value":"E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:15567145, PubMed:15767685, PubMed:15989957, PubMed:17567951, PubMed:18488021, PubMed:19037095, PubMed:19713937, PubMed:20534529, PubMed:30217973). Regulates apoptosis by catalyzing the polyubiquitination and degradation of MCL1 (PubMed:15989957). Mediates monoubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair (PubMed:19713937). Also ubiquitinates the p53/TP53 tumor suppressor and core histones including H1, H2A, H2B, H3 and H4 (PubMed:15567145, PubMed:15767685, PubMed:15989956). Ubiquitinates MFN2 to negatively regulate mitochondrial fusion in response to decreased stearoylation of TFRC (PubMed:26214738). Ubiquitination of MFN2 also takes place following induction of mitophagy; AMBRA1 acts as a cofactor for HUWE1-mediated ubiquitination (PubMed:30217973). Regulates neural differentiation and proliferation by catalyzing the polyubiquitination and degradation of MYCN (PubMed:18488021). May regulate abundance of CDC6 after DNA damage by polyubiquitinating and targeting CDC6 to degradation (PubMed:17567951). Mediates polyubiquitination of isoform 2 of PA2G4 (PubMed:19037095). Acts in concert with MYCBP2 to regulate the circadian clock gene expression by promoting the lithium-induced ubiquitination and degradation of NR1D1 (PubMed:20534529). Binds to an upstream initiator-like sequence in the preprodynorphin gene (By similarity). Mediates HAPSTR1 degradation, but is also a required cofactor in the pathway by which HAPSTR1 governs stress signaling (PubMed:35776542). Acts as a regulator of the JNK and NF-kappa-B signaling pathways by mediating assembly of heterotypic 'Lys-63'-/'Lys-48'-linked branched ubiquitin chains that are then recognized by TAB2: HUWE1 mediates branching of 'Lys-48'-linked chains of substrates initially modified with 'Lys-63'-linked conjugates by TRAF6 (PubMed:27746020). 'Lys-63'-/'Lys-48'-linked branched ubiquitin chains protect 'Lys-63'-linkages from CYLD deubiquitination (PubMed:27746020). Ubiquitinates PPARA in hepatocytes (By similarity)"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.","ecNumber":"2.3.2.26","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15989957"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19713937"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26214738"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"27746020"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30217973"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35776542"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15989957"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19713937"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26214738"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"27746020"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30217973"}],"value":"Protein modification; protein ubiquitination"}],"commentType":"PATHWAY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q7TMY8"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15989956"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17567951"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18488021"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19037095"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19713937"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20534529"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30217973"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35776542"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36631436"}],"value":"Interacts with isoform p14ARF of CDKN2A which strongly inhibits HUWE1 ubiquitin ligase activity. Interacts with MYCN, POLB and CDC6. Interacts with isoform 2 of PA2G4. Interacts with NR1D1 (PubMed:20534529). Interacts with AMBRA1 (PubMed:30217973). Interacts with HAPSTR1 (PubMed:35776542). Interacts with HAPSTR2 (PubMed:36631436). In hepatocytes, interacts with PAQR3; the interaction promotes PPARA poylubiquitination and STUB1-mediated degradation (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"Q7Z6Z7","intActId":"EBI-625934"},"interactantTwo":{"uniProtKBAccession":"Q8N726","geneName":"CDKN2A","intActId":"EBI-625922"},"numberOfExperiments":5,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q7Z6Z7","intActId":"EBI-625934"},"interactantTwo":{"uniProtKBAccession":"P04792","geneName":"HSPB1","intActId":"EBI-352682"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q7Z6Z7","intActId":"EBI-625934"},"interactantTwo":{"uniProtKBAccession":"Q07820","geneName":"MCL1","intActId":"EBI-1003422"},"numberOfExperiments":8,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q7Z6Z7","intActId":"EBI-625934"},"interactantTwo":{"uniProtKBAccession":"P20393","geneName":"NR1D1","intActId":"EBI-2811738"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q7Z6Z7","intActId":"EBI-625934"},"interactantTwo":{"uniProtKBAccession":"P04637","geneName":"TP53","intActId":"EBI-366083"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q7Z6Z7","intActId":"EBI-625934"},"interactantTwo":{"uniProtKBAccession":"Q13107","geneName":"USP4","intActId":"EBI-723290"},"numberOfExperiments":4,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q7Z6Z7","intActId":"EBI-625934"},"interactantTwo":{"uniProtKBAccession":"P40337","geneName":"VHL","intActId":"EBI-301246"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q7Z6Z7-2","intActId":"EBI-10975491"},"interactantTwo":{"uniProtKBAccession":"P27797","geneName":"CALR","intActId":"EBI-1049597"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q7Z6Z7-2","intActId":"EBI-10975491"},"interactantTwo":{"uniProtKBAccession":"P12830","geneName":"CDH1","intActId":"EBI-727477"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q7Z6Z7-2","intActId":"EBI-10975491"},"interactantTwo":{"uniProtKBAccession":"P36957","geneName":"DLST","intActId":"EBI-351007"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q7Z6Z7-2","intActId":"EBI-10975491"},"interactantTwo":{"uniProtKBAccession":"Q8TDX7","geneName":"NEK7","intActId":"EBI-1055945"},"numberOfExperiments":3,"organismDiffer":false}]},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q7TMY8"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30217973"}],"value":"Mainly expressed in the cytoplasm of most tissues, except in the nucleus of spermatogonia, primary spermatocytes and neuronal cells (By similarity). 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