id: Q9UKJ5 gene_symbol: CHIC2 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: CHIC2 (Cysteine-rich hydrophobic domain-containing protein 2; also known as BTL) is a small (165 aa, ~19 kDa) palmitoylated, membrane-associated protein and the defining member of the CHIC family. It contains a single cysteine-rich hydrophobic (CHIC) motif (residues 88-106); palmitoylation within this motif is required for membrane association, and mutation of the cysteine cluster abolishes both palmitoylation and membrane binding. The protein localizes to the plasma membrane and to cytoplasmic vesicles, including a Golgi-like vesicular compartment and scattered vesicles, consistent with a role in membrane-associated vesicle trafficking and secretion. Its N-terminus is an acidic predicted coiled-coil region. The specific molecular function of CHIC2 is not experimentally established. The CHIC2 locus lies at chromosome 4q12 and is recurrently deleted by the cryptic interstitial deletion that fuses FIP1L1 to PDGFRA in hypereosinophilic syndrome/chronic eosinophilic leukemia, where CHIC2 deletion serves as a diagnostic FISH marker; a separate t(4;12)(q12;p13) translocation fuses CHIC2 (BTL) to ETV6 in a form of acute myeloid leukemia. existing_annotations: - term: id: GO:0005798 label: Golgi-associated vesicle evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic (IBA) inference of localization to Golgi-associated vesicle. This is consistent with the experimentally documented Golgi-like vesicular compartment and scattered vesicles described for CHIC2, so the localization is plausible, but the protein is small and membrane-associated rather than functionally "active in" a vesicle lumen, and the IBA transfer is from a broad family model. Keep as a non-core localization annotation. action: KEEP_AS_NON_CORE reason: Plausible vesicular localization consistent with the UniProt note of a Golgi-like vesicular compartment, but inferred phylogenetically rather than directly demonstrated for human CHIC2, and not the core function. supported_by: - reference_id: file:human/CHIC2/CHIC2-uniprot.txt supporting_text: Note=Also present at a Golgi-like vesicular compartment and at scattered vesicles. - term: id: GO:0005886 label: plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic (IBA) inference of plasma membrane localization. This is well supported by experimental evidence that CHIC2 is a palmitoylated, membrane-associated protein localized to the cell membrane, and is independently captured by an IDA annotation from HPA. Accept the plasma membrane localization. action: ACCEPT reason: Plasma membrane localization is directly supported by experimental subcellular localization data and palmitoylation-dependent membrane association. supported_by: - reference_id: file:human/CHIC2/CHIC2-uniprot.txt supporting_text: SUBCELLULAR LOCATION; Cell membrane {ECO:0000269|PubMed:11257495}. - term: id: GO:0005886 label: plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Automated (IEA, multiple-method) annotation of plasma membrane localization, transferred via UniProt-SubCell mapping and the mouse ortholog. Concordant with the experimental cell membrane localization and the HPA IDA annotation. Accept. action: ACCEPT reason: Plasma membrane localization is experimentally supported; the IEA transfer agrees with direct evidence. supported_by: - reference_id: file:human/CHIC2/CHIC2-uniprot.txt supporting_text: SUBCELLULAR LOCATION; Cell membrane {ECO:0000269|PubMed:11257495}. - term: id: GO:0031410 label: cytoplasmic vesicle evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Automated annotation (IEA) of cytoplasmic vesicle localization derived from the UniProt Subcellular Location vocabulary mapping (SL-0088). This is directly supported by the experimental localization of CHIC2 to cytoplasmic vesicles. Accept. action: ACCEPT reason: Cytoplasmic vesicle localization is experimentally documented in the UniProt record (PubMed:11257495). supported_by: - reference_id: file:human/CHIC2/CHIC2-uniprot.txt supporting_text: Cytoplasmic vesicle {ECO:0000269|PubMed:11257495}. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16189514 qualifier: enables review: summary: Bare "protein binding" annotation derived from a high-throughput yeast two-hybrid interactome mapping project (Rual et al.). The interactors reported for CHIC2 from these screens (e.g. OTX1, HOXA1, CATSPER1, PLEKHF2) are not corroborated as specific functional partners and include classic promiscuous Y2H preys. Per curation guidance, bare protein binding is uninformative about molecular function and this is an over-annotation. action: MARK_AS_OVER_ANNOTATED reason: Uninformative bare protein binding from a high-throughput interactome screen; does not define a specific molecular function and partners are not independently validated. supported_by: - reference_id: PMID:16189514 supporting_text: Towards a proteome-scale map of the human protein-protein interaction network. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19060904 qualifier: enables review: summary: Bare "protein binding" annotation from a high-throughput binary interactome mapping benchmarking study (Venkatesan et al.). Provides no specific molecular function and the interaction is not independently corroborated. Over-annotation. action: MARK_AS_OVER_ANNOTATED reason: Uninformative bare protein binding from a high-throughput interactome benchmarking study; no specific functional partner established. supported_by: - reference_id: PMID:19060904 supporting_text: An empirical framework for binary interactome mapping. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: Bare "protein binding" annotation from the HI-II-14 proteome-scale interactome map (Rolland et al.). The numerous CHIC2 interactors from this dataset (keratin-associated proteins, homeodomain transcription factors, etc.) are characteristic of sticky/non-specific Y2H binders and do not define a molecular function. Over-annotation. action: MARK_AS_OVER_ANNOTATED reason: Uninformative bare protein binding from a high-throughput interactome map; partners are largely non-specific Y2H preys with no validated functional relevance. supported_by: - reference_id: PMID:25416956 supporting_text: A proteome-scale map of the human interactome network. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:30886144 qualifier: enables review: summary: Bare "protein binding" annotation derived from a computational, network-based prediction of protein interactions (Kovács et al.), not a direct experimental assay for CHIC2. Provides no specific molecular function and is computationally predicted. Over-annotation. action: MARK_AS_OVER_ANNOTATED reason: Uninformative bare protein binding originating from a computational network prediction; no specific or experimentally validated functional partner. supported_by: - reference_id: PMID:30886144 supporting_text: Network-based prediction of protein interactions. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Bare "protein binding" annotation from the HuRI reference binary interactome map (Luck et al.). This dataset contributes the bulk of CHIC2's ~65 reported IntAct partners, dominated by promiscuous Y2H preys (KRTAPs, LCEs, keratins, homeodomain TFs). None define a specific molecular function for CHIC2. Over-annotation. action: MARK_AS_OVER_ANNOTATED reason: Uninformative bare protein binding from a high-throughput reference interactome; partners are predominantly non-specific binders without validated functional significance. supported_by: - reference_id: PMID:32296183 supporting_text: A reference map of the human binary protein interactome. - term: id: GO:0005794 label: Golgi apparatus evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Automated annotation (IEA) of Golgi apparatus localization transferred from the mouse ortholog via Ensembl Compara. CHIC2 is documented at a Golgi-like vesicular compartment, so association with the Golgi region is plausible, but "Golgi apparatus" is broader and less precise than the documented Golgi-associated vesicular localization. Keep as a non-core localization annotation. action: KEEP_AS_NON_CORE reason: Broad ortholog-transferred Golgi localization; plausible but less precise than the documented Golgi-like vesicular compartment and not the core function. supported_by: - reference_id: file:human/CHIC2/CHIC2-uniprot.txt supporting_text: Note=Also present at a Golgi-like vesicular compartment and at scattered vesicles. - term: id: GO:0005798 label: Golgi-associated vesicle evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Automated annotation (IEA) of Golgi-associated vesicle localization transferred from the mouse ortholog via Ensembl Compara. This is consistent with the experimentally noted Golgi-like vesicular compartment for human CHIC2 and is more precise than the bare Golgi apparatus term. Keep as a non-core localization annotation. action: KEEP_AS_NON_CORE reason: Ortholog-transferred localization consistent with the documented Golgi-like vesicular compartment, but inferred and not the core function. supported_by: - reference_id: file:human/CHIC2/CHIC2-uniprot.txt supporting_text: Note=Also present at a Golgi-like vesicular compartment and at scattered vesicles. - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Direct experimental (IDA) annotation of plasma membrane localization from Human Protein Atlas immunofluorescence curation. This is the strongest evidence for CHIC2 plasma membrane localization and is concordant with palmitoylation-dependent membrane association reported by Cools et al. Accept as a core localization. action: ACCEPT reason: Direct immunofluorescence evidence (HPA) plus palmitoylation-dependent membrane association establish plasma membrane localization. supported_by: - reference_id: file:human/CHIC2/CHIC2-uniprot.txt supporting_text: 'GO:0005886; C:plasma membrane; IDA:HPA.' - reference_id: file:human/CHIC2/CHIC2-uniprot.txt supporting_text: Palmitoylation in the CHIC motif is required for membrane association. core_functions: - description: Palmitoylated, membrane-associated small protein that localizes to the plasma membrane and to cytoplasmic/Golgi-associated vesicles, where it is implicated in membrane-associated vesicle trafficking and secretion. Palmitoylation within the cysteine-rich hydrophobic (CHIC) motif is required for its membrane association. supported_by: - reference_id: file:human/CHIC2/CHIC2-uniprot.txt supporting_text: Cell membrane {ECO:0000269|PubMed:11257495}. Cytoplasmic vesicle {ECO:0000269|PubMed:11257495}. - reference_id: file:human/CHIC2/CHIC2-uniprot.txt supporting_text: Palmitoylation in the CHIC motif is required for membrane association. proposed_new_terms: [] suggested_questions: - question: What is the direct molecular function of CHIC2 at the membrane and on vesicles? Does it act as a scaffold/adapter, a regulator of palmitoylation, or a cargo/trafficking factor? - question: Is CHIC2 functionally related to the Erf4/Golgin-A7 family (which participates in RAB GTPase palmitoylation), and does it have any role in protein palmitoylation or membrane targeting of partner proteins? - question: Does loss of CHIC2 (as occurs in the 4q12 FIP1L1-PDGFRA deletion) contribute to disease phenotype, or is CHIC2 deletion purely a positional marker? suggested_experiments: - description: Acyl-biotin exchange or click-chemistry palmitoylproteomics to confirm CHIC2 palmitoylation sites and identify the responsible palmitoyltransferase(s). - description: Affinity purification-mass spectrometry (AP-MS) under native membrane conditions to identify specific, reproducible CHIC2 interactors and distinguish them from the promiscuous Y2H preys currently annotated. - description: CHIC2 knockout/knockdown in secretory cell models with secretion and vesicle-trafficking assays (e.g. cytokine secretion, surface marker recycling) to test its proposed role in vesicle trafficking. references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt 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 using Ensembl Compara findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:16189514 title: Towards a proteome-scale map of the human protein-protein interaction network. findings: - statement: High-throughput yeast two-hybrid interactome map; source of bare protein binding annotations for CHIC2 with no specific functional partner established. supporting_text: Towards a proteome-scale map of the human protein-protein interaction network. - id: PMID:19060904 title: An empirical framework for binary interactome mapping. findings: - statement: High-throughput binary interactome benchmarking study; source of uninformative protein binding annotation for CHIC2. supporting_text: An empirical framework for binary interactome mapping. - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: - statement: HI-II-14 proteome-scale interactome map; source of multiple non-specific protein binding annotations for CHIC2. supporting_text: A proteome-scale map of the human interactome network. - id: PMID:30886144 title: Network-based prediction of protein interactions. findings: - statement: Computational network-based prediction of interactions; source of a predicted protein binding annotation for CHIC2. supporting_text: Network-based prediction of protein interactions. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: - statement: HuRI reference binary interactome; contributes the bulk of CHIC2's high-throughput Y2H interactors, dominated by promiscuous preys. supporting_text: A reference map of the human binary protein interactome. - id: PMID:11257495 title: A new family of small, palmitoylated, membrane-associated proteins, characterized by the presence of a cysteine-rich hydrophobic motif. findings: - statement: CHIC2 is palmitoylated within the CHIC motif; palmitoylation is required for membrane association, and CHIC2 localizes to the cell membrane and cytoplasmic vesicles including a Golgi-like vesicular compartment. supporting_text: Palmitoylation in the CHIC motif is required for membrane association. - id: file:human/CHIC2/CHIC2-uniprot.txt title: UniProt entry CHIC2_HUMAN (Q9UKJ5) findings: - statement: Documents CHIC2 subcellular localization (cell membrane, cytoplasmic vesicle, Golgi-like vesicular compartment), palmitoylation in the CHIC motif required for membrane association, and the t(4;12) translocation with ETV6. supporting_text: SUBCELLULAR LOCATION; Cell membrane {ECO:0000269|PubMed:11257495}. Cytoplasmic vesicle {ECO:0000269|PubMed:11257495}.