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. In CD8+ T cells, CHIC2 functions as a non-catalytic membrane adapter for the E3 ubiquitin ligase STUB1/CHIP in a complex that post-translationally limits cytokine receptor abundance, including IFNΞ³R1 and IL-27RΞ±, in mouse and human cells. 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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005798 Golgi-associated vesicle | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/CHIC2/CHIC2-uniprot.txt Note=Also present at a Golgi-like vesicular compartment and at scattered vesicles. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Plasma membrane localization is directly supported by experimental subcellular localization data and palmitoylation-dependent membrane association. Supporting Evidence: file:human/CHIC2/CHIC2-uniprot.txt SUBCELLULAR LOCATION; Cell membrane {ECO:0000269|PubMed:11257495}. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | 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. Reason: Plasma membrane localization is experimentally supported; the IEA transfer agrees with direct evidence. Supporting Evidence: file:human/CHIC2/CHIC2-uniprot.txt SUBCELLULAR LOCATION; Cell membrane {ECO:0000269|PubMed:11257495}. |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000044 | ACCEPT | 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. Reason: Cytoplasmic vesicle localization is experimentally documented in the UniProt record (PubMed:11257495). Supporting Evidence: file:human/CHIC2/CHIC2-uniprot.txt Cytoplasmic vesicle {ECO:0000269|PubMed:11257495}. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | 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. Reason: Uninformative bare protein binding from a high-throughput interactome screen; does not define a specific molecular function and partners are not independently validated. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network. |
| GO:0005515 protein binding | IPI PMID:19060904 An empirical framework for binary interactome mapping. | MARK AS OVER ANNOTATED | 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. Reason: Uninformative bare protein binding from a high-throughput interactome benchmarking study; no specific functional partner established. Supporting Evidence: PMID:19060904 An empirical framework for binary interactome mapping. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | 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. Reason: Uninformative bare protein binding from a high-throughput interactome map; partners are largely non-specific Y2H preys with no validated functional relevance. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:30886144 Network-based prediction of protein interactions. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" annotation derived from a computational, network-based prediction of protein interactions (KovΓ‘cs et al.), not a direct experimental assay for CHIC2. Provides no specific molecular function and is computationally predicted. Over-annotation. Reason: Uninformative bare protein binding originating from a computational network prediction; no specific or experimentally validated functional partner. Supporting Evidence: PMID:30886144 Network-based prediction of protein interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | 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. Reason: Uninformative bare protein binding from a high-throughput reference interactome; partners are predominantly non-specific binders without validated functional significance. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. Reason: Broad ortholog-transferred Golgi localization; plausible but less precise than the documented Golgi-like vesicular compartment and not the core function. Supporting Evidence: file:human/CHIC2/CHIC2-uniprot.txt Note=Also present at a Golgi-like vesicular compartment and at scattered vesicles. |
| GO:0005798 Golgi-associated vesicle | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. Reason: Ortholog-transferred localization consistent with the documented Golgi-like vesicular compartment, but inferred and not the core function. Supporting Evidence: file:human/CHIC2/CHIC2-uniprot.txt Note=Also present at a Golgi-like vesicular compartment and at scattered vesicles. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | 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. Reason: Direct immunofluorescence evidence (HPA) plus palmitoylation-dependent membrane association establish plasma membrane localization. Supporting Evidence: file:human/CHIC2/CHIC2-uniprot.txt Palmitoylation in the CHIC motif is required for membrane association. |
| GO:0030674 protein-macromolecule adaptor activity | IPI PMID:40796662 A STUB1-CHIC2 complex inhibits CD8(+) T cells to restrain tu... | NEW | Summary: CHIC2 functions as a membrane-associated adapter for STUB1, bringing the U-box E3 ligase into proximity with cytokine receptors in T cells. Reason: The 2025 STUB1-CHIC2 study directly supports CHIC2 adaptor activity between STUB1 and cytokine receptors. GO:0030674 captures this non-catalytic bridging function without assigning STUB1's U-box ubiquitin ligase activity to CHIC2. Supporting Evidence: PMID:40796662 Mechanistically, STUB1 interacts with the adapter protein CHIC2 to regulate cytokine receptor expression in mouse and human CD8+ T cells. |
| GO:0000151 ubiquitin ligase complex | IPI PMID:40796662 A STUB1-CHIC2 complex inhibits CD8(+) T cells to restrain tu... | NEW | Summary: CHIC2 forms a membrane-associated complex with the U-box E3 ubiquitin ligase STUB1/CHIP in T cells. CHIC2 binds STUB1 through its C-terminal IFRPD motif, the STUB1-CHIC2 complex regulates cytokine receptor levels, and loss of STUB1 or CHIC2 produces non-additive phenotypes. CHIC2 is non-catalytic, so the conservative assertion is membership in a STUB1-containing ubiquitin ligase complex rather than ubiquitin ligase activity. Reason: The 2025 STUB1-CHIC2 study directly supports CHIC2 membership in a STUB1 ubiquitin ligase complex that regulates cytokine receptors in T cells. GOA currently captures only CHIC2 localization and high-throughput bare protein binding; GO:0000151 records the complex-membership aspect without incorrectly assigning E3 catalytic activity to CHIC2. Supporting Evidence: PMID:40796662 CHIC2 could co-precipitate STUB1 but CHIC2 ΞIFRPD could not. PMID:40796662 Collectively, these findings demonstrate that the complex of STUB1 and CHIC2 regulates cytokine receptor expression in T cells. |
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Download this section (compressed HTML)Q: Does CHIC2's STUB1-adapter function extend beyond IFNΞ³R1, IL-27RΞ±, and CSF2RB to additional cytokine receptors, membrane proteins, or cell types?
Q: 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?
Q: Does loss of CHIC2 (as occurs in the 4q12 FIP1L1-PDGFRA deletion) contribute to disease phenotype, or is CHIC2 deletion purely a positional marker?
Experiment: Acyl-biotin exchange or click-chemistry palmitoylproteomics to confirm CHIC2 palmitoylation sites and identify the responsible palmitoyltransferase(s).
Experiment: Affinity purification-mass spectrometry or proximity labeling under native membrane conditions, comparing wild-type CHIC2 with IFRPD- and palmitoylation-defective mutants, to identify reproducible STUB1-dependent and STUB1-independent CHIC2 partners beyond high-throughput Y2H preys.
Experiment: CHIC2 knockout/knockdown with cytokine-receptor ubiquitination, lysosomal flux, secretion, and surface-recycling assays to test which membrane-protein clients depend on CHIC2.
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