id: Q9UNE7 gene_symbol: STUB1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: 'STUB1 (E3 ubiquitin-protein ligase CHIP, C-terminus of HSC70-interacting protein) is a cytoplasmic protein that couples the molecular-chaperone and ubiquitin-proteasome systems. It has a bipartite architecture: an N-terminal tetratricopeptide repeat (TPR) domain that binds the C-terminal EEVD/MEEVD motifs of HSP70/HSC70 and HSP90, and a C-terminal U-box domain that confers RING-type E3 ubiquitin-ligase activity. Acting as a chaperone-associated ''triage'' factor, CHIP ubiquitinates chaperone-bound misfolded or damaged client proteins (in cooperation with E2 enzymes such as UBE2D and UBE2N/UBE2V1) and targets them for proteasomal degradation, while also modulating the activity of the HSP70/HSC70/HSP90 chaperone cycle as a co-chaperone. CHIP functions as a homodimer and additionally participates in protein quality control, ERAD, chaperone-mediated autophagy and mitophagy, and the regulated turnover of numerous specific substrates (e.g. tau, FOXO1, NOS1, POLB, ESR1). Loss of CHIP ubiquitin-ligase activity causes autosomal-recessive (SCAR16) and autosomal-dominant (SCA48) spinocerebellar ataxia.' alternative_products: - name: '1' id: Q9UNE7-1 - name: '2' id: Q9UNE7-2 sequence_note: VSP_015947 existing_annotations: - term: id: GO:0045862 label: positive regulation of proteolysis evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: positive regulation of proteolysis is a downstream process of CHIP's ubiquitin-ligase / quality-control activity. action: KEEP_AS_NON_CORE reason: Plausible process annotation downstream of CHIP's E3-ligase-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: proteasome-mediated ubiquitin-dependent protein catabolic process is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0000209 label: protein polyubiquitination evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: protein polyubiquitination is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0006515 label: protein quality control for misfolded or incompletely synthesized proteins evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: CHIP performs protein quality control by ubiquitinating misfolded chaperone clients for degradation. action: ACCEPT reason: 'Central CHIP function: triage of misfolded chaperone substrates to the proteasome.' supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0030018 label: Z disc evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: 'Z disc: specialized localization (Z-disc / nuclear inclusion body) in particular contexts.' action: KEEP_AS_NON_CORE reason: Context-specific localization; peripheral to CHIP's principal cytoplasmic QC role. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0071218 label: cellular response to misfolded protein evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: 'cellular response to misfolded protein: CHIP participates in cellular stress/misfolded-protein responses via its triage activity.' action: KEEP_AS_NON_CORE reason: Stress/misfolded-protein response context downstream of CHIP's quality-control role; non-core. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin-protein transferase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: CHIP translocates to the nucleus under some conditions; nuclear pool is documented but secondary. action: KEEP_AS_NON_CORE reason: UniProt lists Nucleus (translocates to the nucleus); non-core relative to the cytoplasmic function. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: Translocates to the nucleus - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005739 label: mitochondrion evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: CHIP localizes to mitochondria, linked to mitochondrial QC/mitophagy. action: KEEP_AS_NON_CORE reason: UniProt lists Mitochondrion (by similarity); a specialized non-core localization. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: Mitochondrion - term: id: GO:0007165 label: signal transduction evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: 'signal transduction: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0016567 label: protein ubiquitination evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: protein ubiquitination is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0030163 label: protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: protein catabolic process is a downstream process of CHIP's ubiquitin-ligase / quality-control activity. action: KEEP_AS_NON_CORE reason: Plausible process annotation downstream of CHIP's E3-ligase-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0033554 label: cellular response to stress evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: 'cellular response to stress: CHIP participates in cellular stress/misfolded-protein responses via its triage activity.' action: KEEP_AS_NON_CORE reason: Stress/misfolded-protein response context downstream of CHIP's quality-control role; non-core. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16275660 qualifier: enables review: summary: Interaction with an HSP70/HSP90-family chaperone partner. Bare protein binding is uninformative; better captured as heat shock protein binding. action: MODIFY reason: The WITH partner is an HSP70/HSP90-family chaperone; CHIP's binding is precisely captured as heat shock protein binding, a core co-chaperone function. proposed_replacement_terms: - id: GO:0031072 label: heat shock protein binding supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16293251 qualifier: enables review: summary: Interaction with an HSP70/HSP90-family chaperone partner. Bare protein binding is uninformative; better captured as heat shock protein binding. action: MODIFY reason: The WITH partner is an HSP70/HSP90-family chaperone; CHIP's binding is precisely captured as heat shock protein binding, a core co-chaperone function. proposed_replacement_terms: - id: GO:0031072 label: heat shock protein binding supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16307917 qualifier: enables review: summary: Interaction with an HSP70/HSP90-family chaperone partner. Bare protein binding is uninformative; better captured as Hsp90 protein binding. action: MODIFY reason: The WITH partner is an HSP70/HSP90-family chaperone; CHIP's binding is precisely captured as Hsp90 protein binding, a core co-chaperone function. proposed_replacement_terms: - id: GO:0051879 label: Hsp90 protein binding supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19875381 qualifier: enables review: summary: Interaction with an HSP70/HSP90-family chaperone partner. Bare protein binding is uninformative; better captured as Hsp90 protein binding. action: MODIFY reason: The WITH partner is an HSP70/HSP90-family chaperone; CHIP's binding is precisely captured as Hsp90 protein binding, a core co-chaperone function. proposed_replacement_terms: - id: GO:0051879 label: Hsp90 protein binding supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20029029 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20588253 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20618441 qualifier: enables review: summary: Interaction with an HSP70/HSP90-family chaperone partner. Bare protein binding is uninformative; better captured as heat shock protein binding. action: MODIFY reason: The WITH partner is an HSP70/HSP90-family chaperone; CHIP's binding is precisely captured as heat shock protein binding, a core co-chaperone function. proposed_replacement_terms: - id: GO:0031072 label: heat shock protein binding supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21044950 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21358815 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21360678 qualifier: enables review: summary: Interaction with an HSP70/HSP90-family chaperone partner. Bare protein binding is uninformative; better captured as Hsp90 protein binding. action: MODIFY reason: The WITH partner is an HSP70/HSP90-family chaperone; CHIP's binding is precisely captured as Hsp90 protein binding, a core co-chaperone function. proposed_replacement_terms: - id: GO:0051879 label: Hsp90 protein binding supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22190034 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23973223 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24510904 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24658140 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24981860 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25036637 qualifier: enables review: summary: Interaction with an HSP70/HSP90-family chaperone partner. Bare protein binding is uninformative; better captured as Hsp90 protein binding. action: MODIFY reason: The WITH partner is an HSP70/HSP90-family chaperone; CHIP's binding is precisely captured as Hsp90 protein binding, a core co-chaperone function. proposed_replacement_terms: - id: GO:0051879 label: Hsp90 protein binding supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25260751 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25277244 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26496610 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26871637 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:29513927 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:29568061 qualifier: enables review: summary: Interaction with an HSP70/HSP90-family chaperone partner. Bare protein binding is uninformative; better captured as Hsp70 protein binding. action: MODIFY reason: The WITH partner is an HSP70/HSP90-family chaperone; CHIP's binding is precisely captured as Hsp70 protein binding, a core co-chaperone function. proposed_replacement_terms: - id: GO:0030544 label: Hsp70 protein binding supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31046837 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31515488 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31980649 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32707033 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Interaction with an HSP70/HSP90-family chaperone partner. Bare protein binding is uninformative; better captured as Hsp70 protein binding. action: MODIFY reason: The WITH partner is an HSP70/HSP90-family chaperone; CHIP's binding is precisely captured as Hsp70 protein binding, a core co-chaperone function. proposed_replacement_terms: - id: GO:0030544 label: Hsp70 protein binding supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35266954 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:37045861 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0000165 label: MAPK cascade evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'MAPK cascade: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0002931 label: response to ischemia evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'response to ischemia: CHIP participates in cellular stress/misfolded-protein responses via its triage activity.' action: KEEP_AS_NON_CORE reason: Stress/misfolded-protein response context downstream of CHIP's quality-control role; non-core. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: ubiquitin-dependent protein catabolic process is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0006515 label: protein quality control for misfolded or incompletely synthesized proteins evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: CHIP performs protein quality control by ubiquitinating misfolded chaperone clients for degradation. action: ACCEPT reason: 'Central CHIP function: triage of misfolded chaperone substrates to the proteasome.' supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0010614 label: negative regulation of cardiac muscle hypertrophy evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'negative regulation of cardiac muscle hypertrophy: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0030018 label: Z disc evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: 'Z disc: specialized localization (Z-disc / nuclear inclusion body) in particular contexts.' action: KEEP_AS_NON_CORE reason: Context-specific localization; peripheral to CHIP's principal cytoplasmic QC role. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0030968 label: endoplasmic reticulum unfolded protein response evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'endoplasmic reticulum unfolded protein response: CHIP participates in cellular stress/misfolded-protein responses via its triage activity.' action: KEEP_AS_NON_CORE reason: Stress/misfolded-protein response context downstream of CHIP's quality-control role; non-core. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0031398 label: positive regulation of protein ubiquitination evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: positive regulation of protein ubiquitination is a downstream process of CHIP's ubiquitin-ligase / quality-control activity. action: KEEP_AS_NON_CORE reason: Plausible process annotation downstream of CHIP's E3-ligase-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0031625 label: ubiquitin protein ligase binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: 'ubiquitin protein ligase binding: a specific partner/substrate-binding annotation for CHIP.' action: KEEP_AS_NON_CORE reason: Records a real interaction property of CHIP; non-core relative to its E3-ligase and chaperone-binding core MFs. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0034392 label: negative regulation of smooth muscle cell apoptotic process evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'negative regulation of smooth muscle cell apoptotic process: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0034393 label: positive regulation of smooth muscle cell apoptotic process evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'positive regulation of smooth muscle cell apoptotic process: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0034450 label: ubiquitin-ubiquitin ligase activity evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: CHIP elongates ubiquitin chains on substrates (ubiquitin-ubiquitin ligase / E4-like activity), consistent with its polyubiquitination role. action: ACCEPT reason: Supported by CHIP's documented polyubiquitination of chaperone clients and chain elongation activity. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0034605 label: cellular response to heat evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'cellular response to heat: CHIP participates in cellular stress/misfolded-protein responses via its triage activity.' action: KEEP_AS_NON_CORE reason: Stress/misfolded-protein response context downstream of CHIP's quality-control role; non-core. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0035359 label: negative regulation of peroxisome proliferator activated receptor signaling pathway evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'negative regulation of peroxisome proliferator activated receptor signaling pathway: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0042803 label: protein homodimerization activity evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: CHIP forms a homodimer, required for its E3 ligase activity. action: ACCEPT reason: CHIP functions as a homodimer; homodimerization is a genuine, specific molecular feature. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0043066 label: negative regulation of apoptotic process evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'negative regulation of apoptotic process: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: proteasome-mediated ubiquitin-dependent protein catabolic process is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0051087 label: protein-folding chaperone binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: CHIP binds the folding chaperones HSP70/HSC70/HSP90, consistent with its co-chaperone role. action: ACCEPT reason: Supported by UniProt FUNCTION; chaperone binding underpins CHIP's substrate-triage activity. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0061684 label: chaperone-mediated autophagy evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'chaperone-mediated autophagy: CHIP modulates chaperone-mediated autophagy/mitophagy and chaperone complex assembly.' action: KEEP_AS_NON_CORE reason: Documented co-chaperone-linked process; non-core relative to CHIP's E3-ligase and chaperone-binding MFs. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0071218 label: cellular response to misfolded protein evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'cellular response to misfolded protein: CHIP participates in cellular stress/misfolded-protein responses via its triage activity.' action: KEEP_AS_NON_CORE reason: Stress/misfolded-protein response context downstream of CHIP's quality-control role; non-core. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0071456 label: cellular response to hypoxia evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'cellular response to hypoxia: CHIP participates in cellular stress/misfolded-protein responses via its triage activity.' action: KEEP_AS_NON_CORE reason: Stress/misfolded-protein response context downstream of CHIP's quality-control role; non-core. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:1901526 label: positive regulation of mitophagy evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'positive regulation of mitophagy: CHIP modulates chaperone-mediated autophagy/mitophagy and chaperone complex assembly.' action: KEEP_AS_NON_CORE reason: Documented co-chaperone-linked process; non-core relative to CHIP's E3-ligase and chaperone-binding MFs. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:1904694 label: negative regulation of vascular associated smooth muscle contraction evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: 'negative regulation of vascular associated smooth muscle contraction: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0030512 label: negative regulation of transforming growth factor beta receptor signaling pathway evidence_type: TAS original_reference_id: Reactome:R-HSA-2173788 qualifier: involved_in review: summary: 'negative regulation of transforming growth factor beta receptor signaling pathway: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0038128 label: ERBB2 signaling pathway evidence_type: TAS original_reference_id: Reactome:R-HSA-1227986 qualifier: involved_in review: summary: 'ERBB2 signaling pathway: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: TAS original_reference_id: Reactome:R-HSA-6807134 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: TAS original_reference_id: Reactome:R-HSA-9009308 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005654 label: nucleoplasm evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: CHIP translocates to the nucleus under some conditions; nuclear pool is documented but secondary. action: KEEP_AS_NON_CORE reason: UniProt lists Nucleus (translocates to the nucleus); non-core relative to the cytoplasmic function. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: Translocates to the nucleus - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:17369820 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:23973223 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005739 label: mitochondrion evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: CHIP localizes to mitochondria, linked to mitochondrial QC/mitophagy. action: KEEP_AS_NON_CORE reason: UniProt lists Mitochondrion (by similarity); a specialized non-core localization. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: Mitochondrion - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: EXP original_reference_id: PMID:11557750 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: EXP original_reference_id: PMID:15466472 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0002931 label: response to ischemia evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: 'response to ischemia: CHIP participates in cellular stress/misfolded-protein responses via its triage activity.' action: KEEP_AS_NON_CORE reason: Stress/misfolded-protein response context downstream of CHIP's quality-control role; non-core. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005634 label: nucleus evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: CHIP translocates to the nucleus under some conditions; nuclear pool is documented but secondary. action: KEEP_AS_NON_CORE reason: UniProt lists Nucleus (translocates to the nucleus); non-core relative to the cytoplasmic function. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: Translocates to the nucleus - term: id: GO:0005737 label: cytoplasm evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0034605 label: cellular response to heat evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: 'cellular response to heat: CHIP participates in cellular stress/misfolded-protein responses via its triage activity.' action: KEEP_AS_NON_CORE reason: Stress/misfolded-protein response context downstream of CHIP's quality-control role; non-core. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0071456 label: cellular response to hypoxia evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: 'cellular response to hypoxia: CHIP participates in cellular stress/misfolded-protein responses via its triage activity.' action: KEEP_AS_NON_CORE reason: Stress/misfolded-protein response context downstream of CHIP's quality-control role; non-core. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0035359 label: negative regulation of peroxisome proliferator activated receptor signaling pathway evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: 'negative regulation of peroxisome proliferator activated receptor signaling pathway: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:19713937 qualifier: involved_in review: summary: proteasome-mediated ubiquitin-dependent protein catabolic process is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: TAS original_reference_id: Reactome:R-HSA-1918092 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin-protein transferase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: TAS original_reference_id: Reactome:R-HSA-2187368 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin-protein transferase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: IMP original_reference_id: PMID:23990462 qualifier: involved_in review: summary: ubiquitin-dependent protein catabolic process is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0036503 label: ERAD pathway evidence_type: IMP original_reference_id: PMID:23990462 qualifier: involved_in review: summary: ERAD pathway is a downstream process of CHIP's ubiquitin-ligase / quality-control activity. action: KEEP_AS_NON_CORE reason: Plausible process annotation downstream of CHIP's E3-ligase-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0034393 label: positive regulation of smooth muscle cell apoptotic process evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: 'positive regulation of smooth muscle cell apoptotic process: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0000165 label: MAPK cascade evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: 'MAPK cascade: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19483080 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20724525 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0034392 label: negative regulation of smooth muscle cell apoptotic process evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: 'negative regulation of smooth muscle cell apoptotic process: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0034392 label: negative regulation of smooth muscle cell apoptotic process evidence_type: IMP original_reference_id: PMID:20724525 qualifier: involved_in review: summary: 'negative regulation of smooth muscle cell apoptotic process: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:1901526 label: positive regulation of mitophagy evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: 'positive regulation of mitophagy: CHIP modulates chaperone-mediated autophagy/mitophagy and chaperone complex assembly.' action: KEEP_AS_NON_CORE reason: Documented co-chaperone-linked process; non-core relative to CHIP's E3-ligase and chaperone-binding MFs. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0045862 label: positive regulation of proteolysis evidence_type: IMP original_reference_id: PMID:26634371 qualifier: involved_in review: summary: positive regulation of proteolysis is a downstream process of CHIP's ubiquitin-ligase / quality-control activity. action: KEEP_AS_NON_CORE reason: Plausible process annotation downstream of CHIP's E3-ligase-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26265139 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IDA original_reference_id: PMID:26265139 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:1904294 label: positive regulation of ERAD pathway evidence_type: IMP original_reference_id: PMID:26265139 qualifier: involved_in review: summary: positive regulation of ERAD pathway is a downstream process of CHIP's ubiquitin-ligase / quality-control activity. action: KEEP_AS_NON_CORE reason: Plausible process annotation downstream of CHIP's E3-ligase-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0030512 label: negative regulation of transforming growth factor beta receptor signaling pathway evidence_type: IMP original_reference_id: PMID:15781469 qualifier: involved_in review: summary: 'negative regulation of transforming growth factor beta receptor signaling pathway: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:15781469 qualifier: involved_in review: summary: proteasome-mediated ubiquitin-dependent protein catabolic process is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IMP original_reference_id: PMID:15781469 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0070412 label: R-SMAD binding evidence_type: IPI original_reference_id: PMID:15781469 qualifier: enables review: summary: 'R-SMAD binding: a specific partner/substrate-binding annotation for CHIP.' action: KEEP_AS_NON_CORE reason: Records a real interaction property of CHIP; non-core relative to its E3-ligase and chaperone-binding core MFs. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0042803 label: protein homodimerization activity evidence_type: IPI original_reference_id: PMID:23990462 qualifier: enables review: summary: CHIP forms a homodimer, required for its E3 ligase activity. action: ACCEPT reason: CHIP functions as a homodimer; homodimerization is a genuine, specific molecular feature. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0042803 label: protein homodimerization activity evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables review: summary: CHIP forms a homodimer, required for its E3 ligase activity. action: ACCEPT reason: CHIP functions as a homodimer; homodimerization is a genuine, specific molecular feature. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IDA original_reference_id: PMID:24043303 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:23973223 qualifier: is_active_in review: summary: CHIP translocates to the nucleus under some conditions; nuclear pool is documented but secondary. action: KEEP_AS_NON_CORE reason: UniProt lists Nucleus (translocates to the nucleus); non-core relative to the cytoplasmic function. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: Translocates to the nucleus - term: id: GO:0006513 label: protein monoubiquitination evidence_type: IDA original_reference_id: PMID:24043303 qualifier: involved_in review: summary: protein monoubiquitination is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0050821 label: protein stabilization evidence_type: IDA original_reference_id: PMID:24043303 qualifier: involved_in review: summary: protein stabilization is a downstream process of CHIP's ubiquitin-ligase / quality-control activity. action: KEEP_AS_NON_CORE reason: Plausible process annotation downstream of CHIP's E3-ligase-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0048156 label: tau protein binding evidence_type: NAS original_reference_id: PMID:28386764 qualifier: enables review: summary: CHIP binds tau (MAPT), a chaperone client it ubiquitinates. action: KEEP_AS_NON_CORE reason: Real substrate interaction (tau); informative but a specific client-binding annotation, non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:29883609 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0016567 label: protein ubiquitination evidence_type: IMP original_reference_id: PMID:29883609 qualifier: involved_in review: summary: protein ubiquitination is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IMP original_reference_id: PMID:29883609 qualifier: involved_in review: summary: proteasome-mediated ubiquitin-dependent protein catabolic process is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IMP original_reference_id: PMID:23990462 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:14610072 qualifier: involved_in review: summary: protein ubiquitination is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IDA original_reference_id: PMID:14610072 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16207813 qualifier: enables review: summary: Interaction with an HSP70/HSP90-family chaperone partner. Bare protein binding is uninformative; better captured as Hsp70 protein binding. action: MODIFY reason: The WITH partner is an HSP70/HSP90-family chaperone; CHIP's binding is precisely captured as Hsp70 protein binding, a core co-chaperone function. proposed_replacement_terms: - id: GO:0030544 label: Hsp70 protein binding supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0031072 label: heat shock protein binding evidence_type: IPI original_reference_id: PMID:16207813 qualifier: enables review: summary: CHIP binds heat shock proteins (HSP70/HSC70/HSP90) through its TPR domain. action: ACCEPT reason: Supported by UniProt FUNCTION; binding HSP70/HSP90 chaperones is central to CHIP's triage role. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0051087 label: protein-folding chaperone binding evidence_type: IPI original_reference_id: PMID:16207813 qualifier: enables review: summary: CHIP binds the folding chaperones HSP70/HSC70/HSP90, consistent with its co-chaperone role. action: ACCEPT reason: Supported by UniProt FUNCTION; chaperone binding underpins CHIP's substrate-triage activity. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IGI original_reference_id: PMID:16207813 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0101031 label: protein folding chaperone complex evidence_type: IPI original_reference_id: PMID:16207813 qualifier: part_of review: summary: CHIP associates with HSP70/HSP90 chaperone complexes as a co-chaperone. action: KEEP_AS_NON_CORE reason: CHIP partners with the folding-chaperone machinery; a reasonable complex annotation, non-core relative to its ligase/co-chaperone MFs. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: ISS original_reference_id: PMID:18292230 qualifier: involved_in review: summary: ubiquitin-dependent protein catabolic process is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: IGI original_reference_id: PMID:18292230 qualifier: involved_in review: summary: ubiquitin-dependent protein catabolic process is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: TAS original_reference_id: PMID:19953350 qualifier: involved_in review: summary: proteasome-mediated ubiquitin-dependent protein catabolic process is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27708256 qualifier: enables review: summary: Interaction with an HSP70/HSP90-family chaperone partner. Bare protein binding is uninformative; better captured as heat shock protein binding. action: MODIFY reason: The WITH partner is an HSP70/HSP90-family chaperone; CHIP's binding is precisely captured as heat shock protein binding, a core co-chaperone function. proposed_replacement_terms: - id: GO:0031072 label: heat shock protein binding supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24613385 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0030512 label: negative regulation of transforming growth factor beta receptor signaling pathway evidence_type: IMP original_reference_id: PMID:24613385 qualifier: involved_in review: summary: 'negative regulation of transforming growth factor beta receptor signaling pathway: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0030544 label: Hsp70 protein binding evidence_type: IPI original_reference_id: PMID:24613385 qualifier: enables review: summary: CHIP binds HSP70/HSC70 via its TPR domain; Hsp70 protein binding is a core co-chaperone molecular function. action: ACCEPT reason: Supported by UniProt FUNCTION (modulates Hsp70/Hsc70/Hsp90) and the TPR-domain HSP70-binding role of CHIP. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:24613385 qualifier: involved_in review: summary: proteasome-mediated ubiquitin-dependent protein catabolic process is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0046332 label: SMAD binding evidence_type: IPI original_reference_id: PMID:24613385 qualifier: enables review: summary: 'SMAD binding: a specific partner/substrate-binding annotation for CHIP.' action: KEEP_AS_NON_CORE reason: Records a real interaction property of CHIP; non-core relative to its E3-ligase and chaperone-binding core MFs. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IDA original_reference_id: PMID:24613385 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23431407 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27353360 qualifier: enables review: summary: Interaction with an HSP70/HSP90-family chaperone partner. Bare protein binding is uninformative; better captured as Hsp90 protein binding. action: MODIFY reason: The WITH partner is an HSP70/HSP90-family chaperone; CHIP's binding is precisely captured as Hsp90 protein binding, a core co-chaperone function. proposed_replacement_terms: - id: GO:0051879 label: Hsp90 protein binding supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16809764 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:16809764 qualifier: involved_in review: summary: protein ubiquitination is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0016567 label: protein ubiquitination evidence_type: IMP original_reference_id: PMID:16809764 qualifier: involved_in review: summary: protein ubiquitination is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0031647 label: regulation of protein stability evidence_type: IDA original_reference_id: PMID:16809764 qualifier: involved_in review: summary: regulation of protein stability is a downstream process of CHIP's ubiquitin-ligase / quality-control activity. action: KEEP_AS_NON_CORE reason: Plausible process annotation downstream of CHIP's E3-ligase-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IDA original_reference_id: PMID:16809764 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IMP original_reference_id: PMID:16809764 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0030544 label: Hsp70 protein binding evidence_type: IDA original_reference_id: PMID:23990462 qualifier: enables review: summary: CHIP binds HSP70/HSC70 via its TPR domain; Hsp70 protein binding is a core co-chaperone molecular function. action: ACCEPT reason: Supported by UniProt FUNCTION (modulates Hsp70/Hsc70/Hsp90) and the TPR-domain HSP70-binding role of CHIP. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IDA original_reference_id: PMID:16275660 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IDA original_reference_id: PMID:19103148 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin protein ligase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0000151 label: ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:12150907 qualifier: part_of review: summary: CHIP functions within ubiquitin ligase complexes (with E2 enzymes and chaperones). action: ACCEPT reason: Consistent with CHIP's E3 ligase activity acting in complex with E2s and chaperone-bound substrates. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0001664 label: G protein-coupled receptor binding evidence_type: IPI original_reference_id: PMID:12150907 qualifier: enables review: summary: 'G protein-coupled receptor binding: a specific partner/substrate-binding annotation for CHIP.' action: KEEP_AS_NON_CORE reason: Records a real interaction property of CHIP; non-core relative to its E3-ligase and chaperone-binding core MFs. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IDA original_reference_id: PMID:12150907 qualifier: located_in review: summary: CHIP participates in ER-associated degradation (ERAD) of certain substrates. action: KEEP_AS_NON_CORE reason: ER context reflects CHIP's ERAD role (e.g. CHRNA3, CYP3A4); non-core localization. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0031625 label: ubiquitin protein ligase binding evidence_type: IPI original_reference_id: PMID:12150907 qualifier: enables review: summary: 'ubiquitin protein ligase binding: a specific partner/substrate-binding annotation for CHIP.' action: KEEP_AS_NON_CORE reason: Records a real interaction property of CHIP; non-core relative to its E3-ligase and chaperone-binding core MFs. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0000151 label: ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:16275660 qualifier: part_of review: summary: CHIP functions within ubiquitin ligase complexes (with E2 enzymes and chaperones). action: ACCEPT reason: Consistent with CHIP's E3 ligase activity acting in complex with E2s and chaperone-bound substrates. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0000209 label: protein polyubiquitination evidence_type: IDA original_reference_id: PMID:16275660 qualifier: involved_in review: summary: protein polyubiquitination is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-1918092 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-2187368 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-2187375 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-6807134 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9009308 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9009309 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9688831 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9688838 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9796368 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9796387 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22366786 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0000151 label: ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:16307917 qualifier: part_of review: summary: CHIP functions within ubiquitin ligase complexes (with E2 enzymes and chaperones). action: ACCEPT reason: Consistent with CHIP's E3 ligase activity acting in complex with E2s and chaperone-bound substrates. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0051865 label: protein autoubiquitination evidence_type: IDA original_reference_id: PMID:16307917 qualifier: involved_in review: summary: protein autoubiquitination is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0070534 label: protein K63-linked ubiquitination evidence_type: IDA original_reference_id: PMID:16307917 qualifier: involved_in review: summary: protein K63-linked ubiquitination is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0000209 label: protein polyubiquitination evidence_type: IMP original_reference_id: PMID:19713937 qualifier: involved_in review: summary: protein polyubiquitination is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: IMP original_reference_id: PMID:19713937 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin-protein transferase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: IMP original_reference_id: PMID:19713937 qualifier: involved_in review: summary: ubiquitin-dependent protein catabolic process is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19423554 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: IDA original_reference_id: PMID:15466472 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin-protein transferase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0051865 label: protein autoubiquitination evidence_type: IDA original_reference_id: PMID:18042044 qualifier: involved_in review: summary: protein autoubiquitination is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0019900 label: kinase binding evidence_type: IPI original_reference_id: PMID:17512523 qualifier: enables review: summary: 'kinase binding: a specific partner/substrate-binding annotation for CHIP.' action: KEEP_AS_NON_CORE reason: Records a real interaction property of CHIP; non-core relative to its E3-ligase and chaperone-binding core MFs. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:16831871 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0006515 label: protein quality control for misfolded or incompletely synthesized proteins evidence_type: IDA original_reference_id: PMID:16831871 qualifier: involved_in review: summary: CHIP performs protein quality control by ubiquitinating misfolded chaperone clients for degradation. action: ACCEPT reason: 'Central CHIP function: triage of misfolded chaperone substrates to the proteasome.' supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0031398 label: positive regulation of protein ubiquitination evidence_type: IDA original_reference_id: PMID:16831871 qualifier: involved_in review: summary: positive regulation of protein ubiquitination is a downstream process of CHIP's ubiquitin-ligase / quality-control activity. action: KEEP_AS_NON_CORE reason: Plausible process annotation downstream of CHIP's E3-ligase-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0042405 label: nuclear inclusion body evidence_type: IDA original_reference_id: PMID:16831871 qualifier: located_in review: summary: 'nuclear inclusion body: specialized localization (Z-disc / nuclear inclusion body) in particular contexts.' action: KEEP_AS_NON_CORE reason: Context-specific localization; peripheral to CHIP's principal cytoplasmic QC role. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0051787 label: misfolded protein binding evidence_type: IDA original_reference_id: PMID:16831871 qualifier: enables review: summary: CHIP recognizes misfolded chaperone-bound clients for ubiquitination. action: ACCEPT reason: Supported by UniProt FUNCTION (targets misfolded chaperone substrates); misfolded protein binding underlies substrate selection. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0071218 label: cellular response to misfolded protein evidence_type: IDA original_reference_id: PMID:16831871 qualifier: involved_in review: summary: 'cellular response to misfolded protein: CHIP participates in cellular stress/misfolded-protein responses via its triage activity.' action: KEEP_AS_NON_CORE reason: Stress/misfolded-protein response context downstream of CHIP's quality-control role; non-core. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0090035 label: positive regulation of chaperone-mediated protein complex assembly evidence_type: IDA original_reference_id: PMID:16831871 qualifier: involved_in review: summary: 'positive regulation of chaperone-mediated protein complex assembly: CHIP modulates chaperone-mediated autophagy/mitophagy and chaperone complex assembly.' action: KEEP_AS_NON_CORE reason: Documented co-chaperone-linked process; non-core relative to CHIP's E3-ligase and chaperone-binding MFs. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0051879 label: Hsp90 protein binding evidence_type: IDA original_reference_id: PMID:11146632 qualifier: enables review: summary: CHIP binds HSP90 via its TPR domain; Hsp90 protein binding is a core co-chaperone molecular function. action: ACCEPT reason: Supported by UniProt FUNCTION (modulates Hsp70/Hsc70/Hsp90); CHIP is a TPR co-chaperone of HSP90. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0034450 label: ubiquitin-ubiquitin ligase activity evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables review: summary: CHIP elongates ubiquitin chains on substrates (ubiquitin-ubiquitin ligase / E4-like activity), consistent with its polyubiquitination role. action: ACCEPT reason: Supported by CHIP's documented polyubiquitination of chaperone clients and chain elongation activity. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0019899 label: enzyme binding evidence_type: IPI original_reference_id: PMID:16280320 qualifier: enables review: summary: 'enzyme binding: a specific partner/substrate-binding annotation for CHIP.' action: KEEP_AS_NON_CORE reason: Records a real interaction property of CHIP; non-core relative to its E3-ligase and chaperone-binding core MFs. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:11146632 qualifier: enables review: summary: Protein interaction captured by an interactome/IPI study (substrate or partner). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (often a CHIP substrate or partner) but bare protein binding is uninformative and not elevated to core. supported_by: - reference_id: file:human/STUB1/STUB1-goa.tsv supporting_text: GO:0005515 protein binding - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:10330192 qualifier: located_in review: summary: CHIP is predominantly cytoplasmic/cytosolic, where it triages chaperone clients. action: ACCEPT reason: Matches UniProt subcellular location; cytoplasm/cytosol is the principal compartment. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0030544 label: Hsp70 protein binding evidence_type: IDA original_reference_id: PMID:10330192 qualifier: enables review: summary: CHIP binds HSP70/HSC70 via its TPR domain; Hsp70 protein binding is a core co-chaperone molecular function. action: ACCEPT reason: Supported by UniProt FUNCTION (modulates Hsp70/Hsc70/Hsp90) and the TPR-domain HSP70-binding role of CHIP. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - term: id: GO:0030911 label: TPR domain binding evidence_type: IDA original_reference_id: PMID:11146632 qualifier: enables review: summary: CHIP's TPR domain mediates chaperone binding; this annotation reflects TPR-mediated interactions. action: KEEP_AS_NON_CORE reason: Real TPR-mediated interaction property; captured more informatively by the Hsp70/Hsp90 binding terms. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: The TPR domain is essential for ubiquitination mediated by - term: id: GO:0031398 label: positive regulation of protein ubiquitination evidence_type: IDA original_reference_id: PMID:11146632 qualifier: involved_in review: summary: positive regulation of protein ubiquitination is a downstream process of CHIP's ubiquitin-ligase / quality-control activity. action: KEEP_AS_NON_CORE reason: Plausible process annotation downstream of CHIP's E3-ligase-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0031943 label: regulation of glucocorticoid metabolic process evidence_type: IDA original_reference_id: PMID:11146632 qualifier: involved_in review: summary: 'regulation of glucocorticoid metabolic process: a substrate-specific/pleiotropic process attributed to CHIP via degradation of a particular client.' action: KEEP_AS_NON_CORE reason: Downstream, substrate-specific physiological consequence of CHIP-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0032436 label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:11146632 qualifier: involved_in review: summary: positive regulation of proteasomal ubiquitin-dependent protein catabolic process is a downstream process of CHIP's ubiquitin-ligase / quality-control activity. action: KEEP_AS_NON_CORE reason: Plausible process annotation downstream of CHIP's E3-ligase-mediated degradation; non-core relative to the catalytic MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0030674 label: protein-macromolecule adaptor activity evidence_type: TAS original_reference_id: PMID:16307917 qualifier: enables review: summary: 'protein-macromolecule adaptor activity: a specific partner/substrate-binding annotation for CHIP.' action: KEEP_AS_NON_CORE reason: Records a real interaction property of CHIP; non-core relative to its E3-ligase and chaperone-binding core MFs. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0000209 label: protein polyubiquitination evidence_type: IDA original_reference_id: PMID:15781469 qualifier: involved_in review: summary: protein polyubiquitination is a direct outcome of CHIP's E3 ubiquitin-ligase activity on its substrates. action: ACCEPT reason: Directly tied to CHIP's polyubiquitination/ubiquitination activity (U-box E3 ligase). supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: TAS original_reference_id: PMID:16307917 qualifier: enables review: summary: STUB1/CHIP is a U-box-type E3 ubiquitin-protein ligase; ubiquitin-protein transferase activity is a core molecular function. action: ACCEPT reason: Directly supported by UniProt FUNCTION; CHIP is a well-characterized U-box E3 ligase that ubiquitinates chaperone clients for degradation. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - term: id: GO:0031371 label: ubiquitin conjugating enzyme complex evidence_type: TAS original_reference_id: PMID:16307917 qualifier: part_of review: summary: CHIP acts together with E2 ubiquitin-conjugating enzymes (e.g. UBE2N/UBE2D). action: KEEP_AS_NON_CORE reason: Reflects CHIP-E2 cooperation; non-core relative to its E3 ligase MF. supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs using sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs by Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic GO annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:10330192 title: 'Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions.' findings: [] - id: PMID:11146632 title: 'The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins.' findings: [] - id: PMID:11557750 title: 'CHIP is a U-box-dependent E3 ubiquitin ligase: identification of Hsc70 as a target for ubiquitylation.' findings: [] - id: PMID:12150907 title: CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity. findings: [] - id: PMID:14610072 title: 'Dimerization of the human E3 ligase CHIP via a coiled-coil domain is essential for its activity.' findings: [] - id: PMID:15466472 title: 'Ubiquitylation of neuronal nitric-oxide synthase by CHIP, a chaperone-dependent E3 ligase.' findings: [] - id: PMID:15781469 title: CHIP controls the sensitivity of transforming growth factor-beta signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation. findings: [] - id: PMID:16207813 title: BAG-2 acts as an inhibitor of the chaperone-associated ubiquitin ligase CHIP. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: GOA-anchored (this PMID supports GO:0061630 ubiquitin protein ligase activity, GO:0051087 protein-folding chaperone binding, and GO:0101031 protein folding chaperone complex in STUB1-goa.tsv); supports CHIP/STUB1 as the chaperone-associated ubiquitin ligase, anchoring its E3 ligase and co-chaperone core functions. - id: PMID:16275660 title: Identification of VCP/p97, carboxyl terminus of Hsp70-interacting protein (CHIP), and amphiphysin II interaction partners using membrane-based human proteome arrays. findings: [] - id: PMID:16280320 title: 'DPM1, the catalytic subunit of dolichol-phosphate mannose synthase, is tethered to and stabilized on the endoplasmic reticulum membrane by DPM3.' findings: [] - id: PMID:16293251 title: CHIP interacts with heat shock factor 1 during heat stress. findings: [] - id: PMID:16307917 title: 'Chaperoned ubiquitylation--crystal structures of the CHIP U box E3 ubiquitin ligase and a CHIP-Ubc13-Uev1a complex.' findings: [] - id: PMID:16809764 title: Histone deacetylase 8 safeguards the human ever-shorter telomeres 1B (hEST1B) protein from ubiquitin-mediated degradation. findings: [] - id: PMID:16831871 title: 'CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation.' findings: [] - id: PMID:17369820 title: 'The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy.' findings: [] - id: PMID:17512523 title: 'Parkin interacts with LIM Kinase 1 and reduces its cofilin-phosphorylation activity via ubiquitination.' findings: [] - id: PMID:18042044 title: 'Two different classes of E2 ubiquitin-conjugating enzymes are required for the mono-ubiquitination of proteins and elongation by polyubiquitin chains with a specific topology.' findings: [] - id: PMID:18292230 title: Akt and CHIP coregulate tau degradation through coordinated interactions. findings: [] - id: PMID:19103148 title: CYP3A4 ubiquitination by gp78 (the tumor autocrine motility factor receptor, AMFR) and CHIP E3 ligases. findings: [] - id: PMID:19423554 title: 'Functional interaction of DYX1C1 with estrogen receptors suggests involvement of hormonal pathways in dyslexia.' findings: [] - id: PMID:19483080 title: C terminus of Hsc70-interacting protein promotes smooth muscle cell proliferation and survival through ubiquitin-mediated degradation of FoxO1. findings: [] - id: PMID:19713937 title: 'Ubiquitin ligase ARF-BP1/Mule modulates base excision repair.' findings: [] - id: PMID:19875381 title: A proteomic investigation of ligand-dependent HSP90 complexes reveals CHORDC1 as a novel ADP-dependent HSP90-interacting protein. findings: [] - id: PMID:19953350 title: 'Brain distribution of carboxy terminus of Hsc70-interacting protein (CHIP) and its nuclear translocation in cultured cortical neurons following heat stress or oxygen-glucose deprivation.' findings: [] - id: PMID:20029029 title: Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6. findings: [] - id: PMID:20588253 title: 'CHIP-dependent termination of MEKK2 regulates temporal ERK activation required for proper hyperosmotic response.' findings: [] - id: PMID:20618441 title: CHIP participates in protein triage decisions by preferentially ubiquitinating Hsp70-bound substrates. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cached publication title matches PubMed; establishes CHIP/STUB1's protein-quality-control triage role - preferentially ubiquitinating misfolded chaperone substrates for degradation, a core function. - id: PMID:20724525 title: 'Novel role of C terminus of Hsc70-interacting protein (CHIP) ubiquitin ligase on inhibiting cardiac apoptosis and dysfunction via regulating ERK5-mediated degradation of inducible cAMP early repressor.' findings: [] - id: PMID:21044950 title: Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells. findings: [] - id: PMID:21358815 title: 'Ubiquitinylation of α-synuclein by carboxyl terminus Hsp70-interacting protein (CHIP) is regulated by Bcl-2-associated athanogene 5 (BAG5).' findings: [] - id: PMID:21360678 title: Label-free quantitative proteomics and SAINT analysis enable interactome mapping for the human Ser/Thr protein phosphatase 5. findings: [] - id: PMID:22190034 title: Global landscape of HIV-human protein complexes. findings: [] - id: PMID:22366786 title: Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy. findings: [] - id: PMID:23431407 title: Distinct roles of molecular chaperones HSP90α and HSP90β in the biogenesis of KCNQ4 channels. findings: [] - id: PMID:23973223 title: 'The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3.' findings: [] - id: PMID:23990462 title: 'Endoplasmic reticulum protein quality control is determined by cooperative interactions between Hsp/c70 protein and the CHIP E3 ligase.' findings: [] - id: PMID:24043303 title: 'The ubiquitin ligase CHIP prevents SirT6 degradation through noncanonical ubiquitination.' findings: [] - id: PMID:24510904 title: Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. findings: [] - id: PMID:24613385 title: Hsp70 and Hsp90 oppositely regulate TGF-β signaling through CHIP/Stub1. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: GOA-anchored (this PMID supports GO:0061630 ubiquitin protein ligase activity IDA, GO:0030544 Hsp70 protein binding IPI, and GO:0043161 proteasome-mediated degradation in STUB1-goa.tsv); directly establishes all three CHIP/STUB1 core functions - E3 ligase activity, Hsp70 co-chaperone binding, and chaperone-coupled proteasomal degradation. - id: PMID:24658140 title: The mammalian-membrane two-hybrid assay (MaMTH) for probing membrane-protein interactions in human cells. findings: [] - id: PMID:24981860 title: Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation. findings: [] - id: PMID:25036637 title: A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. findings: [] - id: PMID:25260751 title: The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines. findings: [] - id: PMID:25277244 title: The functional landscape of Hsp27 reveals new cellular processes such as DNA repair and alternative splicing and proposes novel anticancer targets. findings: [] - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: [] - id: PMID:26265139 title: UBXN2A regulates nicotinic receptor degradation by modulating the E3 ligase activity of CHIP. findings: [] - id: PMID:26496610 title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances. findings: [] - id: PMID:26634371 title: Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy. findings: [] - id: PMID:26871637 title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. findings: [] - id: PMID:27353360 title: The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding. findings: [] - id: PMID:27708256 title: ARD1-mediated Hsp70 acetylation balances stress-induced protein refolding and degradation. findings: [] - id: PMID:28386764 title: Roles of tau protein in health and disease. findings: [] - id: PMID:29513927 title: Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins. findings: [] - id: PMID:29568061 title: An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. findings: [] - id: PMID:29883609 title: 'PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylation-Dependent Proteasomal Degradation.' findings: [] - id: PMID:31046837 title: Parkinson's disease-associated LRRK2-G2019S mutant acts through regulation of SERCA activity to control ER stress in astrocytes. findings: [] - id: PMID:31515488 title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. findings: [] - id: PMID:31980649 title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D). findings: [] - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:32707033 title: Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. findings: [] - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:35266954 title: The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity. findings: [] - id: PMID:37045861 title: Interactome dynamics of RAF1-BRAF kinase monomers and dimers. findings: [] - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] - id: Reactome:R-HSA-1227986 title: Reactome pathway R-HSA-1227986 findings: [] - id: Reactome:R-HSA-1918092 title: Reactome pathway R-HSA-1918092 findings: [] - id: Reactome:R-HSA-2173788 title: Reactome pathway R-HSA-2173788 findings: [] - id: Reactome:R-HSA-2187368 title: Reactome pathway R-HSA-2187368 findings: [] - id: Reactome:R-HSA-2187375 title: Reactome pathway R-HSA-2187375 findings: [] - id: Reactome:R-HSA-6807134 title: Reactome pathway R-HSA-6807134 findings: [] - id: Reactome:R-HSA-9009308 title: Reactome pathway R-HSA-9009308 findings: [] - id: Reactome:R-HSA-9009309 title: Reactome pathway R-HSA-9009309 findings: [] - id: Reactome:R-HSA-9688831 title: Reactome pathway R-HSA-9688831 findings: [] - id: Reactome:R-HSA-9688838 title: Reactome pathway R-HSA-9688838 findings: [] - id: Reactome:R-HSA-9796368 title: Reactome pathway R-HSA-9796368 findings: [] - id: Reactome:R-HSA-9796387 title: Reactome pathway R-HSA-9796387 findings: [] core_functions: - description: U-box-type E3 ubiquitin-protein ligase that, in cooperation with E2 enzymes, ubiquitinates chaperone-bound misfolded/damaged client proteins and targets them for proteasomal degradation. molecular_function: id: GO:0061630 label: ubiquitin protein ligase activity locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone - description: 'HSP70/HSC70/HSP90 co-chaperone: via its TPR domain CHIP binds these chaperones and modulates their activity, coupling client triage to the chaperone cycle.' molecular_function: id: GO:0030544 label: Hsp70 protein binding locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: chaperone complexes, including Hsp70, Hsc70 and Hsp90 - description: 'Protein quality control: CHIP recognizes misfolded chaperone substrates and routes them to ubiquitin-dependent proteasomal degradation, integrating folding and degradation decisions.' molecular_function: id: GO:0004842 label: ubiquitin-protein transferase activity locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: file:human/STUB1/STUB1-uniprot.txt supporting_text: E3 ubiquitin-protein ligase which targets misfolded chaperone proposed_new_terms: [] suggested_questions: - question: How does CHIP discriminate between chaperone clients destined for refolding versus ubiquitination/degradation, and which features of the chaperone-client complex bias this triage decision? - question: How do the SCAR16 (recessive) and SCA48 (dominant) STUB1 variants differ mechanistically (loss of ligase activity, loss of dimerization, or dominant-negative effects on the chaperone-ligase axis)? - question: To what extent are CHIP's many substrate-specific physiological roles (cardiac, immune, vascular) driven by tissue-specific chaperone/co-chaperone context versus intrinsic substrate selectivity? suggested_experiments: - description: Reconstitute CHIP-mediated ubiquitination in vitro with HSP70/HSP90-bound model clients and defined E2s to dissect how TPR-domain chaperone binding and U-box catalysis are coordinated, using TPR and U-box point mutants. - description: Compare client/substrate profiles (ubiquitinome and stability proteomics) in CHIP-knockout versus SCAR16/SCA48 patient-variant knock-in cells to map disease-relevant substrate dysregulation. - description: Quantify CHIP homodimerization and its requirement for E3 activity using engineered monomeric variants, correlating with chaperone binding and substrate turnover.