CHIC2

UniProt ID: Q9UKJ5
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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 Review

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 (Kovács 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
GO:0005886; C:plasma membrane; IDA:HPA.
file:human/CHIC2/CHIC2-uniprot.txt
Palmitoylation in the CHIC motif is required for membrane association.

Core Functions

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.

Supporting Evidence:
  • file:human/CHIC2/CHIC2-uniprot.txt
    Cell membrane {ECO:0000269|PubMed:11257495}. Cytoplasmic vesicle {ECO:0000269|PubMed:11257495}.
  • file:human/CHIC2/CHIC2-uniprot.txt
    Palmitoylation in the CHIC motif is required for membrane association.

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:16189514
Towards a proteome-scale map of the human protein-protein interaction network.
  • High-throughput yeast two-hybrid interactome map; source of bare protein binding annotations for CHIC2 with no specific functional partner established.
    "Towards a proteome-scale map of the human protein-protein interaction network."
PMID:19060904
An empirical framework for binary interactome mapping.
  • High-throughput binary interactome benchmarking study; source of uninformative protein binding annotation for CHIC2.
    "An empirical framework for binary interactome mapping."
PMID:25416956
A proteome-scale map of the human interactome network.
  • HI-II-14 proteome-scale interactome map; source of multiple non-specific protein binding annotations for CHIC2.
    "A proteome-scale map of the human interactome network."
PMID:30886144
Network-based prediction of protein interactions.
  • Computational network-based prediction of interactions; source of a predicted protein binding annotation for CHIC2.
    "Network-based prediction of protein interactions."
PMID:32296183
A reference map of the human binary protein interactome.
  • HuRI reference binary interactome; contributes the bulk of CHIC2's high-throughput Y2H interactors, dominated by promiscuous preys.
    "A reference map of the human binary protein interactome."
PMID:11257495
A new family of small, palmitoylated, membrane-associated proteins, characterized by the presence of a cysteine-rich hydrophobic motif.
  • 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.
    "Palmitoylation in the CHIC motif is required for membrane association."
file:human/CHIC2/CHIC2-uniprot.txt
UniProt entry CHIC2_HUMAN (Q9UKJ5)
  • 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.
    "SUBCELLULAR LOCATION; Cell membrane {ECO:0000269|PubMed:11257495}. Cytoplasmic vesicle {ECO:0000269|PubMed:11257495}."

Suggested Questions for Experts

Q: 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?

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?

Suggested Experiments

Experiment: Acyl-biotin exchange or click-chemistry palmitoylproteomics to confirm CHIC2 palmitoylation sites and identify the responsible palmitoyltransferase(s).

Experiment: 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.

Experiment: 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.

📚 Additional Documentation

Notes

(CHIC2-notes.md)

CHIC2 (Cysteine-rich hydrophobic domain-containing protein 2) — Review Notes

UniProt: Q9UKJ5 (CHIC2_HUMAN); Gene: CHIC2; Synonym: BTL ("BrX-like translocated in leukemia"); 165 aa; HGNC:1935; locus 4q12.

Core biology

  • CHIC2 is a small (165 aa, ~19 kDa) protein and the founding/defining member of the CHIC family, characterized by a single cysteine-rich hydrophobic (CHIC) motif (residues 88–106) [file:human/CHIC2/CHIC2-uniprot.txt MOTIF 88..106].
  • It is palmitoylated within the CHIC motif, and palmitoylation is required for membrane association PMID:11257495. Mutagenesis of the cysteine cluster (88-CGCLCCCC-95 → SGSLSSSS) causes loss of palmitoylation and abolishes membrane association [file:human/CHIC2/CHIC2-uniprot.txt MUTAGEN 88..95].
  • Subcellular location (experimental, IDA): cell membrane / plasma membrane and cytoplasmic vesicle; also present at a Golgi-like vesicular compartment and at scattered vesicles [PMID:11257495; file:human/CHIC2/CHIC2-uniprot.txt SUBCELLULAR LOCATION].
  • The N-terminus (1–26) is predicted coiled-coil (acidic, EEEDEE-rich) [file:human/CHIC2/CHIC2-uniprot.txt COILED 1..26].
  • Pfam: Erf4 (PF10256); InterPro: CHIC1/2 (IPR039735), Golgin_A_7/ERF4 (IPR019383); PANTHER PTHR13005. The Erf4/Golgin-A7 relationship suggests possible roles in vesicle/Golgi-associated trafficking and protein palmitoylation/processing, but a defined molecular function for CHIC2 is not established.

Molecular function — poorly defined

  • The molecular function of CHIC2 is not experimentally established. It has been implicated broadly in cytokine secretion and vesicle trafficking (literature/secondary sources), consistent with its palmitoylated membrane/vesicle localization, but no direct biochemical activity has been demonstrated.
  • All GO molecular-function annotations in GOA are bare protein binding (GO:0005515, IPI) derived from high-throughput interactome / Y2H mapping projects (CCSB/Human Reference Interactome and network-prediction studies):
  • PMID:16189514 — Rual et al., "Towards a proteome-scale map of the human protein-protein interaction network" (HT Y2H).
  • PMID:19060904 — Venkatesan et al., "An empirical framework for binary interactome mapping" (HT Y2H benchmarking).
  • PMID:25416956 — Rolland et al., "A proteome-scale map of the human interactome network" (HI-II-14).
  • PMID:30886144 — Kovács et al., "Network-based prediction of protein interactions" (computational prediction).
  • PMID:32296183 — Luck et al., "A reference map of the human binary protein interactome" (HuRI).
  • The UniProt IntAct interaction list (65 partners) is dominated by sticky/promiscuous Y2H preys (numerous KRTAPs, LCEs, keratins, homeodomain TFs such as OTX1, HOXA1, MEOX2, POU4F2) with NbExp=3, which are classic non-specific binders. None of these define a specific molecular function and none are independently corroborated as functional partners. Treated as over-annotations of bare protein binding.

Disease / clinical relevance

  • CHIC2 lies at 4q12. A cryptic interstitial deletion at 4q12 fuses FIP1L1 to PDGFRA, producing the constitutively active FIP1L1-PDGFRA tyrosine kinase that drives hypereosinophilic syndrome / chronic eosinophilic leukemia. Deletion of CHIC2 is used clinically as a FISH marker (CHIC2 deletion) for this fusion; CHIC2 loss is a positional marker and is not established as causal in the disease phenotype.
  • A separate chromosomal translocation t(4;12)(q12;p13) fuses CHIC2 (BTL) to ETV6 in a form of acute myeloid leukemia [PMID:10477709 (UniProt RN[1]); file:human/CHIC2/CHIC2-uniprot.txt DISEASE]. The functional consequence for CHIC2 itself is unclear.

GO annotation assessment summary

  • Cellular component (localization): Well supported as a membrane/vesicle-associated protein.
  • plasma membrane (GO:0005886) — IDA (HPA, GO_REF:0000052) and IBA: ACCEPT/supported; consistent with PMID:11257495 cell membrane localization.
  • cytoplasmic vesicle (GO:0031410) — IEA from UniProt SubCell (SL-0088): supported by PMID:11257495 "Cytoplasmic vesicle"; KEEP.
  • Golgi-associated vesicle (GO:0005798) — IBA + IEA(Ensembl ortholog): consistent with "Golgi-like vesicular compartment" note; reasonable but inferred, keep as non-core / accept localization.
  • Golgi apparatus (GO:0005794) — IEA(Ensembl ortholog, GO_REF:0000107): broader/less precise than the documented Golgi-like vesicular compartment; KEEP_AS_NON_CORE.
  • Molecular function: All protein binding (GO:0005515) IPI from high-throughput interactome screens — uninformative bare protein binding → MARK_AS_OVER_ANNOTATED (per curation guidance to avoid bare protein binding).

Tentative core function

Palmitoylated, membrane/vesicle-associated small protein localized to the plasma membrane and cytoplasmic/Golgi-associated vesicles; implicated in intracellular vesicle trafficking/secretion. Molecular mechanism undefined.

Pn Notes

(CHIC2-pn-notes.md)

CHIC2 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9UKJ5
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • 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/core annotation action counts: ACCEPT: 4; KEEP_AS_NON_CORE: 3; MARK_AS_OVER_ANNOTATED: 5

PN Consistency Summary

  • Consistency: PARTIAL CONFLICT. The review (and notes) state CHIC2's molecular function is undefined and frame it purely as a palmitoylated membrane/vesicle protein; it makes NO mention of STUB1 or an E3-ligase-complex role. The PN annotation rests on PMID:40796662, which is NOT cited in the review. Per PubMed, PMID:40796662 (Nat Immunol 2025, DOI) establishes a real STUB1-CHIC2 complex in which CHIC2 is the non-catalytic adapter for the E3 ligase STUB1 regulating cytokine-receptor levels in CD8 T cells. So the PN is built on a genuine 2025 finding the review predates/misses.
  • PN story / NEW pressure: PN asserts a role (member of an E3 ligase complex via STUB1) absent from existing GO and from the review. GO:0000151 "ubiquitin ligase complex" verified real (OLS) and confirmed new_to_goa (CHIC2-goa.tsv has only localization + bare protein-binding). This is a defensible ADD as part_of GO:0000151, supported by PMID:40796662. CHIC2 is non-catalytic, so the group-level complex-membership mapping (rather than ligase activity) is the correct, conservative target.
  • Evidence alignment: No overlap. PN cites PMID:40796662 (the defining STUB1-CHIC2 paper); the review cites only HT-interactome PMIDs (16189514, 19060904, 25416956, 30886144, 32296183, all MARK_AS_OVER_ANNOTATED) plus PMID:11257495 (palmitoylation). The PN reference is the more functionally informative one and is missing from the review.
  • Verdict: UNDER-CAPTURED by review — PN ADD is justified. Recommended edits: [YAML] add PMID:40796662 to references and add a NEW/proposed annotation GO:0000151 (part_of, "STUB1-CHIC2 complex") and an adapter/molecular-function note; [REF] flag that the review's "function undefined" framing is now superseded by the STUB1-CHIC2 adapter finding.

Full Consistency Review

  • UniProt: Q9UKJ5 · batch: proteostasis-batch-2026-06-07 · review status: COMPLETE
  • PN placement: UPS|E3 ubiquitin and UBL ligases|idiosyncratic UBOX complex|STUB1/CHIC2 complex|noncatalytic ; PN-node mapping: group (idiosyncratic UBOX complex)→GO:0000151 ubiquitin ligase complex (new_to_goa). Subtype/type/branch = no_mapping; class context_only.
  • Consistency: PARTIAL CONFLICT. The review (and notes) state CHIC2's molecular function is undefined and frame it purely as a palmitoylated membrane/vesicle protein; it makes NO mention of STUB1 or an E3-ligase-complex role. The PN annotation rests on PMID:40796662, which is NOT cited in the review. Per PubMed, PMID:40796662 (Nat Immunol 2025, DOI) establishes a real STUB1-CHIC2 complex in which CHIC2 is the non-catalytic adapter for the E3 ligase STUB1 regulating cytokine-receptor levels in CD8 T cells. So the PN is built on a genuine 2025 finding the review predates/misses.
  • PN story / NEW pressure: PN asserts a role (member of an E3 ligase complex via STUB1) absent from existing GO and from the review. GO:0000151 "ubiquitin ligase complex" verified real (OLS) and confirmed new_to_goa (CHIC2-goa.tsv has only localization + bare protein-binding). This is a defensible ADD as part_of GO:0000151, supported by PMID:40796662. CHIC2 is non-catalytic, so the group-level complex-membership mapping (rather than ligase activity) is the correct, conservative target.
  • Mapping strategy: Mapping is sound and well-judged: assigns complex membership (GO:0000151) not catalytic activity to a non-catalytic adapter; holds the E3 class context_only to avoid over-propagation. No change needed to the node.
  • Evidence alignment: No overlap. PN cites PMID:40796662 (the defining STUB1-CHIC2 paper); the review cites only HT-interactome PMIDs (16189514, 19060904, 25416956, 30886144, 32296183, all MARK_AS_OVER_ANNOTATED) plus PMID:11257495 (palmitoylation). The PN reference is the more functionally informative one and is missing from the review.
  • Verdict: UNDER-CAPTURED by review — PN ADD is justified. Recommended edits: [YAML] add PMID:40796662 to references and add a NEW/proposed annotation GO:0000151 (part_of, "STUB1-CHIC2 complex") and an adapter/molecular-function note; [REF] flag that the review's "function undefined" framing is now superseded by the STUB1-CHIC2 adapter finding.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07
  • review_yaml: genes/human/CHIC2/CHIC2-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | idiosyncratic UBOX complex | STUB1/CHIC2 complex | noncatalytic

  • UniProt: Q9UKJ5
  • In branches: UPS
  • Signature domains: (none)
  • Auxiliary domains: (none)
  • PN references (titles):
    • 40796662
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic UBOX complex|STUB1/CHIC2 complex|noncatalytic
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic UBOX complex|STUB1/CHIC2 complex
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic UBOX complex
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0000151 ubiquitin ligase complex]
      rationale: This PN group is an E3 ligase complex bucket. The safest shared GO target is ubiquitin ligase complex membership rather than assigning catalytic activity to every subunit.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

  • GO:0000151 ubiquitin ligase complex | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic UBOX complex

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
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}.