id: Q14011
gene_symbol: CIRBP
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  CIRBP (cold-inducible RNA-binding protein; also known as A18 hnRNP / CIRP) is a small
  (172 aa) stress-responsive RNA-binding protein built from an N-terminal canonical RRM
  domain and a C-terminal intrinsically disordered, arginine/glycine-rich (RGG/RG) region
  that also contains an arginine-serine-tyrosine (RSY) motif. It is induced by mild
  hypothermia (cold shock) as well as UV irradiation, hypoxia and other cellular stresses.
  CIRBP binds primarily the 3'-untranslated regions of target transcripts and acts post-
  transcriptionally to stabilize stress- and survival-related mRNAs (e.g. RPA2, thioredoxin/TXN)
  and to modulate their translation; it associates with ribosomes and the translation
  initiation factor eIF4G1 and can enhance translation of its stabilized targets while acting
  as a translational repressor when sequestered in cytoplasmic stress granules. CIRBP is
  predominantly nuclear (nucleoplasm) at steady state and shuttles to the cytoplasm and into
  stress granules upon stress; nuclear import is mediated by Transportin-1 (recognizing the
  RG/RGG region) and Transportin-3 (recognizing the RSY motif), and its localization and phase
  behavior are tuned by arginine methylation (PRMT1) and phosphorylation (CK2, GSK3B, SRPK1).
  Functionally it contributes to cold-induced suppression of cell proliferation and to
  protection against genotoxic/oxidative stress. A distinct, extensively studied moonlighting
  activity is that of extracellular CIRP (eCIRP): when released from stressed or dying cells it
  acts as a damage-associated molecular pattern that engages receptors such as TLR4/MD2,
  TREM-1 and IL-6R to promote inflammation.
alternative_products:
- name: '1'
  id: Q14011-1
- name: '2'
  id: Q14011-2
  sequence_note: VSP_056402, VSP_056403
- name: '3'
  id: Q14011-3
  sequence_note: VSP_056895, VSP_056403
existing_annotations:
- term:
    id: GO:0003729
    label: mRNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) annotation that CIRBP binds mRNA. This is well supported by direct
      experimental evidence for binding the 3'-UTRs of specific mRNAs and by unbiased mRNA-
      interactome capture studies, and reflects the core molecular function of the protein.
    action: ACCEPT
    reason: >-
      CIRBP is a bona fide mRNA-binding protein; the IBA term is at an appropriate level of
      generality and is corroborated by IDA/HDA evidence (mRNA 3'-UTR binding; RNA-binding
      atlases).
    supported_by:
    - reference_id: PMID:11574538
      supporting_text: A18 hnRNP binds specifically to the 3'-untranslated region of RPA2 transcript independently of its poly(A) tail
- term:
    id: GO:0000398
    label: mRNA splicing, via spliceosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) propagation of a splicing role from the broader hnRNP/RBM family.
      There is no direct experimental evidence that CIRBP functions in pre-mRNA splicing;
      its characterized activities are 3'-UTR binding, mRNA stabilization and translational
      control. CIRBP co-purifies with the spliceosome in high-throughput interaction maps,
      but copurification is not evidence of a splicing function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The defining and experimentally supported functions of CIRBP are post-transcriptional
      (mRNA stability and translation), not splicing. The comprehensive literature review of
      CIRBP does not attribute a splicing function to it. PANTHER PAINT analysis (see
      file:families/PTHR48034/PTHR48034-review.md) shows this IBA descends from internal node
      PTN000391532, whose splicing IBD is seeded only by transformer-2/RBMX splicing factors
      (TRA2A Q13595, TRA2B P62995, RBMX P38159, Drosophila tra2 FBgn0003742, rat Tra2
      RGD:1306751/RGD:1565256). CIRBP's own subfamily node (PTN008729690) carries only the
      generic, correct 'mRNA binding' term. The splicing annotation is therefore an
      over-propagation across a functional-divergence boundary (splicing-factor branch vs.
      cold-inducible mRNA-stability branch).
    additional_reference_ids:
    - file:families/PTHR48034/PTHR48034-review.md
    supported_by:
    - reference_id: PMID:22365833
      supporting_text: More than 200 proteins copurify with spliceosomes
- term:
    id: GO:0005681
    label: spliceosomal complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      Phylogenetic (IBA) localization to the spliceosomal complex, inherited from
      spliceosome-associated paralogs. CIRBP appears in spliceosome protein-interaction maps,
      but it is not a recognized core spliceosomal component and the primary literature does
      not describe it acting within the spliceosome.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      As with the splicing process term, there is no direct evidence CIRBP is a functional
      part of the spliceosome; the annotation reflects family-level propagation rather than
      CIRBP-specific data. Per PANTHER PAINT (file:families/PTHR48034/PTHR48034-review.md),
      the spliceosomal-complex IBD at node PTN000391532 is seeded only by the splicing
      factors TRA2B (P62995), RBMX (P38159) and rat Tra2 (RGD:1306751); it was propagated to
      the diverged cold-inducible CIRBP/RBM3 branch, whose subfamily node carries only
      'mRNA binding'.
    additional_reference_ids:
    - file:families/PTHR48034/PTHR48034-review.md
    supported_by:
    - reference_id: PMID:22365833
      supporting_text: More than 200 proteins copurify with spliceosomes
- term:
    id: GO:0003676
    label: nucleic acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based electronic annotation of generic nucleic acid binding, derived from the
      RRM domain. Correct but very general; the more specific RNA-binding / mRNA 3'-UTR
      binding terms better capture the function.
    action: ACCEPT
    reason: >-
      The term is accurate (CIRBP has an RRM and binds nucleic acid) and a broad IEA parent is
      acceptable; more specific terms are present elsewhere in the annotation set.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based electronic annotation of RNA binding from the RRM domain. Strongly
      supported by direct and high-throughput evidence.
    action: ACCEPT
    reason: >-
      CIRBP is an RRM-containing RNA-binding protein; the term is correct and well supported.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation (UniProt subcellular location mapping) placing CIRBP in the
      nucleoplasm. Consistent with immunofluorescence showing nucleoplasmic localization at
      steady state and with the IDA HPA annotation.
    action: ACCEPT
    reason: >-
      Nucleoplasmic localization is well established for CIRBP under unstressed conditions.
    supported_by:
    - reference_id: PMID:9151692
      supporting_text: CIRP was localized in the nucleoplasm of BALB/3T3 mouse fibroblasts
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation of cytoplasmic localization. CIRBP translocates from the nucleus
      to the cytoplasm upon UV and other stresses, where it carries out much of its mRNA-
      stabilizing/translational function; supported by IDA (PMID:11574538).
    action: ACCEPT
    reason: >-
      Stress-induced cytoplasmic localization is experimentally documented.
    supported_by:
    - reference_id: PMID:11574538
      supporting_text: is induced and translocated from the nuclei to the cytoplasm after exposure to UV radiation
- term:
    id: GO:0009409
    label: response to cold
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA machine-learning electronic annotation of response to cold. This is the defining
      property of CIRBP (cold-inducible) and is independently supported by the founding study
      and a TAS annotation.
    action: ACCEPT
    reason: >-
      Cold-inducibility and a role in the cold-stress response are the hallmark features of
      CIRBP.
    supported_by:
    - reference_id: PMID:9151692
      supporting_text: CIRP plays an essential role in cold-induced growth suppression of mouse fibroblasts
- term:
    id: GO:0017148
    label: negative regulation of translation
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      Inferred electronically from the translation repressor activity (GO:0030371) annotation.
      Consistent with CIRBP acting as a translational repressor when recruited into stress
      granules and via its RGG domain.
    action: ACCEPT
    reason: >-
      CIRBP can repress translation (notably in stress granules), so this process term is
      appropriate; it is context-dependent and complementary to its positive regulation of
      translation of stabilized targets.
    supported_by:
    - reference_id: file:human/CIRBP/CIRBP-deep-research-falcon.md
      supporting_text: under severe stress, CIRBP is recruited to stress granules
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Protein-protein interaction (high-throughput interactome) annotation. Uninformative as a
      molecular function; retained as a valid interaction record (partner RBMX).
    action: ACCEPT
    reason: >-
      Valid interaction evidence but the generic 'protein binding' term conveys no specific
      molecular function; kept as-is per convention.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16713569
  qualifier: enables
  review:
    summary: >-
      Interaction with ATXN1 from an inherited-ataxia interaction network screen. Uninformative
      generic term; retained as an interaction record.
    action: ACCEPT
    reason: >-
      Valid interaction evidence; 'protein binding' is non-specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: >-
      High-throughput interaction (partner HNRNPK). Uninformative generic term; retained as an
      interaction record.
    action: ACCEPT
    reason: >-
      Valid interaction evidence; 'protein binding' is non-specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22365833
  qualifier: enables
  review:
    summary: >-
      Interaction detected in the human spliceosome protein-interaction map (partner HNRNPK).
      Uninformative generic term; also note this is the source of the spliceosome-association
      (over-annotated) terms above.
    action: ACCEPT
    reason: >-
      Valid interaction evidence; 'protein binding' is non-specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Multiple interactions from a proteome-scale binary interactome map (partners include
      SNRPA, RBMX, RBMY, HNRNPK, KHDRBS2, LNX1). Uninformative generic term; retained.
    action: ACCEPT
    reason: >-
      Valid interaction evidence; 'protein binding' is non-specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29892012
  qualifier: enables
  review:
    summary: >-
      High-throughput interaction (partner HNRNPK). Uninformative generic term; retained.
    action: ACCEPT
    reason: >-
      Valid interaction evidence; 'protein binding' is non-specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: >-
      High-throughput interaction (partners SNRPA, KHDRBS2). Uninformative generic term;
      retained.
    action: ACCEPT
    reason: >-
      Valid interaction evidence; 'protein binding' is non-specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32234784
  qualifier: enables
  review:
    summary: >-
      Interaction with the nuclear import receptors Transportin-1 (TNPO1) and Transportin-3
      (TNPO3). Although recorded as generic 'protein binding', this interaction is functionally
      meaningful: TNPO1 recognizes the RG/RGG region and TNPO3 the RSY motif to mediate CIRBP
      nuclear import.
    action: ACCEPT
    reason: >-
      Valid and functionally important interaction; the generic term itself is non-specific but
      correct.
    supported_by:
    - reference_id: PMID:32234784
      supporting_text: both TNPO1 and Transportin-3 (TNPO3) recognize two nonclassical NLSs within the cold-inducible RNA-binding protein (CIRBP)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      High-throughput binary interactome interactions (partners HNRNPK, SRSF3). Uninformative
      generic term; retained.
    action: ACCEPT
    reason: >-
      Valid interaction evidence; 'protein binding' is non-specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      Interaction from a neurodegenerative-disease interactome map (partner ATXN1). Uninformative
      generic term; retained.
    action: ACCEPT
    reason: >-
      Valid interaction evidence; 'protein binding' is non-specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      High-throughput interaction (partner TNPO3) from a cell-specific interactome remodeling
      study. Uninformative generic term; retained.
    action: ACCEPT
    reason: >-
      Valid interaction evidence; 'protein binding' is non-specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: >-
      Endogenous-tagging (OpenCell) interaction (partner TNPO3). Uninformative generic term;
      retained.
    action: ACCEPT
    reason: >-
      Valid interaction evidence; 'protein binding' is non-specific.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct immunofluorescence (Human Protein Atlas) annotation of nucleoplasmic localization,
      consistent with the steady-state nuclear localization of CIRBP.
    action: ACCEPT
    reason: >-
      Well-supported localization; CIRBP is predominantly nucleoplasmic when unstressed.
    supported_by:
    - reference_id: PMID:9151692
      supporting_text: CIRP was localized in the nucleoplasm of BALB/3T3 mouse fibroblasts
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:16791210
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomic (dynamic proteomics) annotation of nuclear localization.
      Consistent with the established predominantly nuclear localization of CIRBP.
    action: ACCEPT
    reason: >-
      Nuclear localization is well established.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  qualifier: enables
  review:
    summary: >-
      CIRBP identified as an RNA-binding protein in an unbiased mRNA-interactome capture atlas
      (UV crosslinking + oligo(dT)) in HeLa cells. Strong, direct high-throughput support for
      RNA binding.
    action: ACCEPT
    reason: >-
      Robust experimental evidence that CIRBP binds mRNA in cells.
    supported_by:
    - reference_id: PMID:22658674
      supporting_text: We identify 860 proteins that qualify as RBPs by biochemical and statistical criteria
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22681889
  qualifier: enables
  review:
    summary: >-
      CIRBP identified in a second, independent mRNA-bound proteome study (HEK293, photoreactive
      nucleotide crosslinking). Corroborates RNA binding.
    action: ACCEPT
    reason: >-
      Independent high-throughput evidence for RNA binding.
    supported_by:
    - reference_id: PMID:22681889
      supporting_text: nearly one-third were not previously annotated as RNA binding
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity transfer of nuclear localization from an ortholog. Consistent with
      direct evidence (IDA/HDA) for nuclear localization of CIRBP.
    action: ACCEPT
    reason: >-
      Nuclear localization is independently supported by experimental evidence.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity transfer of cytoplasmic localization. Consistent with stress-induced
      nucleus-to-cytoplasm translocation documented by IDA.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is independently supported by experimental evidence.
- term:
    id: GO:0009411
    label: response to UV
  evidence_type: IDA
  original_reference_id: PMID:11574538
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence that CIRBP (A18 hnRNP) is induced by UV, translocates to the cytoplasm,
      and stabilizes UV/stress-responsive transcripts; cells with reduced CIRBP are more
      sensitive to UV. Strong support for a role in the UV response.
    action: ACCEPT
    reason: >-
      Experimentally demonstrated participation in the genotoxic/UV stress response.
    supported_by:
    - reference_id: PMID:11574538
      supporting_text: is induced and translocated from the nuclei to the cytoplasm after exposure to UV radiation
- term:
    id: GO:0010494
    label: cytoplasmic stress granule
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity transfer of stress granule localization. CIRBP is recruited into
      cytoplasmic stress granules upon various stresses (methylation of its RGG motif is a
      prerequisite), so this localization is well supported by the broader literature.
    action: ACCEPT
    reason: >-
      Stress granule localization of CIRBP is documented; the ISS term is consistent with
      direct studies of SG recruitment.
    supported_by:
    - reference_id: file:human/CIRBP/CIRBP-deep-research-falcon.md
      supporting_text: Methylation of arginine residues within the RGG motif is essential for CIRBP recruitment to stress granules
- term:
    id: GO:0030371
    label: translation repressor activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity transfer of translation repressor activity. The C-terminal RGG domain
      mediates translational repression, and CIRBP acts as a translational repressor when
      recruited into stress granules. This is context-dependent: CIRBP can also enhance
      translation of specific stabilized targets via eIF4G1.
    action: ACCEPT
    reason: >-
      Translational repression is a documented activity of CIRBP, complementing its positive
      regulation of translation of stabilized transcripts.
    supported_by:
    - reference_id: file:human/CIRBP/CIRBP-deep-research-falcon.md
      supporting_text: under severe stress, CIRBP is recruited to stress granules
- term:
    id: GO:0034063
    label: stress granule assembly
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer of a role in stress granule assembly. UniProt notes that
      CIRBP promotes assembly of stress granules when overexpressed, and its RGG-dependent
      phase separation underlies SG recruitment.
    action: ACCEPT
    reason: >-
      Consistent with CIRBP's documented role in promoting/participating in stress granule
      formation.
    supported_by:
    - reference_id: file:human/CIRBP/CIRBP-deep-research-falcon.md
      supporting_text: Methylation of arginine residues within the RGG motif is essential for CIRBP recruitment to stress granules
- term:
    id: GO:0070181
    label: small ribosomal subunit rRNA binding
  evidence_type: IDA
  original_reference_id: PMID:11574538
  qualifier: enables
  review:
    summary: >-
      IDA annotation of small ribosomal subunit rRNA binding citing PMID:11574538. The cached
      abstract of this paper describes CIRBP binding to mRNA 3'-UTRs (RPA2, TXN), not to
      ribosomal RNA; the full text is not available in the cache, so the specific evidence for
      rRNA binding cannot be verified here. CIRBP does associate with ribosomes (PMID:16513844),
      but ribosome association is not equivalent to small-subunit rRNA binding.
    action: UNDECIDED
    reason: >-
      The supporting evidence for rRNA (as opposed to mRNA) binding cannot be confirmed from the
      available (abstract-only) text, and the abstract foregrounds mRNA 3'-UTR binding. Per
      curation guidance, an experimental annotation should not be removed on incomplete evidence;
      full text is required to confirm or correct this term.
    supported_by:
    - reference_id: PMID:11574538
      supporting_text: A18 hnRNP binds specifically to the 3'-untranslated region of RPA2 transcript independently of its poly(A) tail
- term:
    id: GO:0003730
    label: mRNA 3'-UTR binding
  evidence_type: IDA
  original_reference_id: PMID:11574538
  qualifier: enables
  review:
    summary: >-
      Direct demonstration that CIRBP (A18 hnRNP) binds specifically to the 3'-UTR of the RPA2
      transcript. This is the most specific and informative molecular-function annotation for
      CIRBP and represents a core function.
    action: ACCEPT
    reason: >-
      Sequence-specific 3'-UTR binding is the experimentally defined molecular activity through
      which CIRBP regulates target mRNA stability and translation.
    supported_by:
    - reference_id: PMID:11574538
      supporting_text: A18 hnRNP binds specifically to the 3'-untranslated region of RPA2 transcript independently of its poly(A) tail
- term:
    id: GO:0003730
    label: mRNA 3'-UTR binding
  evidence_type: IDA
  original_reference_id: PMID:16513844
  qualifier: enables
  review:
    summary: >-
      Independent direct evidence that the CIRBP RRM and RGG domains both bind the thioredoxin
      (TXN) 3'-UTR. Corroborates the core 3'-UTR-binding molecular function.
    action: ACCEPT
    reason: >-
      Second experimental demonstration of sequence-specific 3'-UTR binding (TXN), reinforcing
      this as a core function.
    supported_by:
    - reference_id: PMID:16513844
      supporting_text: the heterogenous ribonucleoprotein A18 (hnRNP A18) RNA Binding Domain (RBD) and the arginine, glycine (RGG) rich domain can bind TRX 3'-untranslated region (3'-UTR) independently
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16513844
  qualifier: enables
  review:
    summary: >-
      Interaction with EIF4G1 (eukaryotic translation initiation factor 4 gamma 1). Recorded as
      generic 'protein binding', but mechanistically important: CIRBP interacts with eIF4G to
      promote translation of its target transcripts and associates with ribosomes.
    action: ACCEPT
    reason: >-
      Valid and functionally significant interaction; the generic term is correct but
      uninformative.
    supported_by:
    - reference_id: PMID:16513844
      supporting_text: hnRNP A18 increases TRX translation and interacts with the eukaryotic Initiation Factor 4G (eIF4G)
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:11574538
  qualifier: located_in
  review:
    summary: >-
      Direct evidence of nuclear localization of CIRBP, which translocates to the cytoplasm
      after UV exposure. Consistent with all other localization evidence.
    action: ACCEPT
    reason: >-
      Experimentally documented nuclear localization (steady state).
    supported_by:
    - reference_id: PMID:11574538
      supporting_text: is induced and translocated from the nuclei to the cytoplasm after exposure to UV radiation
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:11574538
  qualifier: located_in
  review:
    summary: >-
      Direct evidence of cytoplasmic localization of CIRBP following UV-induced translocation,
      where it stabilizes target transcripts and enhances their translation.
    action: ACCEPT
    reason: >-
      Experimentally documented stress-induced cytoplasmic localization.
    supported_by:
    - reference_id: PMID:11574538
      supporting_text: is induced and translocated from the nuclei to the cytoplasm after exposure to UV radiation
- term:
    id: GO:0045727
    label: positive regulation of translation
  evidence_type: IDA
  original_reference_id: PMID:11574538
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence that overexpression of CIRBP increases the stability of target mRNAs and
      consequently enhances their translation in a dose-dependent manner. A core post-
      transcriptional regulatory function for its stabilized targets.
    action: ACCEPT
    reason: >-
      Experimentally demonstrated enhancement of translation of stabilized target mRNAs.
    supported_by:
    - reference_id: PMID:11574538
      supporting_text: Overexpression of A18 hnRNP increases the mRNAs stability and consequently enhances translation in a dose-dependent manner
- term:
    id: GO:0048255
    label: mRNA stabilization
  evidence_type: IDA
  original_reference_id: PMID:11574538
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence that CIRBP increases the stability of bound target mRNAs (e.g. RPA2, TXN),
      a core function executed through 3'-UTR binding.
    action: ACCEPT
    reason: >-
      Experimentally demonstrated mRNA-stabilizing activity; this is a central, defining
      function of CIRBP.
    supported_by:
    - reference_id: PMID:11574538
      supporting_text: Overexpression of A18 hnRNP increases the mRNAs stability and consequently enhances translation in a dose-dependent manner
- term:
    id: GO:0009409
    label: response to cold
  evidence_type: TAS
  original_reference_id: PMID:9151692
  qualifier: involved_in
  review:
    summary: >-
      Traceable author statement from the founding study, which showed that CIRP is induced on
      cooling (37 to 32 C) and mediates cold-induced suppression of cell growth. Defines the
      hallmark cold-stress role of CIRBP.
    action: ACCEPT
    reason: >-
      The cold-stress response is the original and defining function of CIRBP, supported by
      direct experiments in the cited paper.
    supported_by:
    - reference_id: PMID:9151692
      supporting_text: CIRP plays an essential role in cold-induced growth suppression of mouse fibroblasts
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: TAS
  original_reference_id: file:human/CIRBP/CIRBP-deep-research-falcon.md
  qualifier: located_in
  review:
    summary: >-
      Not present in current GOA. Extensively documented in the literature: under severe stress
      (hemorrhagic shock, sepsis, ischemia-reperfusion) CIRBP is released from cells into the
      extracellular space as extracellular CIRP (eCIRP) via unconventional secretion. This is a
      moonlighting/released location distinct from its intracellular RNA-binding role.
    action: NEW
    reason: >-
      The extracellular localization of CIRBP (eCIRP) is a well-established, heavily studied
      aspect of its biology that is missing from the current annotation set; adding it captures
      the location where its DAMP function occurs.
    supported_by:
    - reference_id: file:human/CIRBP/CIRBP-deep-research-falcon.md
      supporting_text: is released into the extracellular space as extracellular CIRP
- term:
    id: GO:0050729
    label: positive regulation of inflammatory response
  evidence_type: TAS
  original_reference_id: file:human/CIRBP/CIRBP-deep-research-falcon.md
  qualifier: involved_in
  review:
    summary: >-
      Not present in current GOA. As a released damage-associated molecular pattern (eCIRP),
      CIRBP promotes inflammation by engaging receptors including TLR4/MD2, TREM-1 and IL-6R,
      driving pro-inflammatory cytokine production and inflammatory cell death. This is a
      moonlighting function of the extracellular protein rather than its evolved intracellular
      RNA-binding activity.
    action: NEW
    reason: >-
      The pro-inflammatory DAMP activity of eCIRP is one of the most studied aspects of CIRBP
      biology and is absent from the existing annotations; it should be captured (as a non-core,
      extracellular function).
    supported_by:
    - reference_id: file:human/CIRBP/CIRBP-deep-research-falcon.md
      supporting_text: When released extracellularly as eCIRP, it functions as a potent DAMP, engaging TLR4, TREM-1, and IL-6R to drive inflammation
core_functions:
- description: >-
    Sequence-specific binding of target mRNA 3'-untranslated regions to stabilize stress- and
    survival-related transcripts (e.g. RPA2, thioredoxin/TXN) and enhance their translation,
    acting in both nucleus and cytoplasm and through interaction with the translation machinery
    (eIF4G1, ribosomes).
  molecular_function:
    id: GO:0003730
    label: mRNA 3'-UTR binding
  directly_involved_in:
  - id: GO:0048255
    label: mRNA stabilization
  - id: GO:0045727
    label: positive regulation of translation
  - id: GO:0009411
    label: response to UV
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:11574538
    supporting_text: A18 hnRNP binds specifically to the 3'-untranslated region of RPA2 transcript independently of its poly(A) tail
    reference_section_type: ABSTRACT
  - reference_id: PMID:11574538
    supporting_text: Overexpression of A18 hnRNP increases the mRNAs stability and consequently enhances translation in a dose-dependent manner
    reference_section_type: ABSTRACT
  - reference_id: PMID:16513844
    supporting_text: hnRNP A18 increases TRX translation and interacts with the eukaryotic Initiation Factor 4G (eIF4G)
    reference_section_type: ABSTRACT
- description: >-
    Cold-inducible RNA-binding protein of the cold/cellular stress response: induced on cooling
    and by other stresses, CIRBP contributes to cold-induced suppression of cell proliferation
    and protects cells against genotoxic stress.
  molecular_function:
    id: GO:0003729
    label: mRNA binding
  directly_involved_in:
  - id: GO:0009409
    label: response to cold
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:9151692
    supporting_text: CIRP plays an essential role in cold-induced growth suppression of mouse fibroblasts
    reference_section_type: ABSTRACT
- description: >-
    Upon stress, CIRBP is recruited (via its methylated RGG domain) into cytoplasmic stress
    granules, where it acts as a translational repressor; this stress-granule sequestration is
    part of the protein's stress-response localization switching.
  molecular_function:
    id: GO:0030371
    label: translation repressor activity
  directly_involved_in:
  - id: GO:0034063
    label: stress granule assembly
  - id: GO:0017148
    label: negative regulation of translation
  locations:
  - id: GO:0010494
    label: cytoplasmic stress granule
  supported_by:
  - reference_id: file:human/CIRBP/CIRBP-deep-research-falcon.md
    supporting_text: Methylation of arginine residues within the RGG motif is essential for CIRBP recruitment to stress granules
    reference_section_type: OTHER
proposed_new_terms: []
suggested_questions:
- question: >-
    Does CIRBP genuinely bind small ribosomal subunit rRNA (GO:0070181), or does the existing
    IDA annotation reflect its documented association with ribosomes/mRNPs rather than direct
    rRNA binding?
  experts:
  - Carrier F
  - Yang R
- question: >-
    Should the extracellular DAMP activity of CIRBP (eCIRP) be formally captured in GO as a
    moonlighting function distinct from its intracellular RNA-binding role, and what is the most
    appropriate term set (e.g. extracellular space, positive regulation of inflammatory response,
    Toll-like receptor binding)?
  experts:
  - Aziz M
  - Wang P
suggested_experiments:
- hypothesis: >-
    CIRBP's core in vivo molecular function is sequence-specific 3'-UTR binding that stabilizes a
    defined regulon of stress/survival transcripts, rather than a general role in splicing.
  description: >-
    Perform transcriptome-wide CLIP-seq (e.g. iCLIP/eCLIP) for endogenous CIRBP under basal and
    cold/UV stress, integrated with RNA stability (e.g. SLAM-seq) and ribosome profiling, to
    define direct binding sites (3'-UTR enrichment), stabilized targets, and translational
    effects; test for any splicing changes to evaluate the spliceosome-associated annotations.
  experiment_type: CLIP-seq with RNA stability and ribosome profiling
- hypothesis: >-
    The GO:0070181 small ribosomal subunit rRNA binding annotation overstates a ribosome
    association; CIRBP does not directly contact 18S rRNA.
  description: >-
    Use in vitro binding assays (EMSA/filter binding, SPR) with purified CIRBP against defined
    mRNA 3'-UTR fragments versus 18S rRNA, plus CLIP recovery of rRNA versus mRNA, to determine
    whether direct small-subunit rRNA binding occurs.
  experiment_type: in vitro RNA-binding specificity assay
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
    by curator judgment of sequence similarity
  findings: []
- 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:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:11574538
  title: The UV-inducible RNA-binding protein A18 (A18 hnRNP) plays a protective role
    in the genotoxic stress response.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary study establishing CIRBP/A18 hnRNP UV induction, nucleus-to-cytoplasm
      translocation, specific 3'-UTR binding to RPA2 and TXN, mRNA stabilization and enhanced
      translation. Supports the core 3'-UTR-binding/stabilization/translation annotations.
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome map; supports only generic protein binding.
- id: PMID:16513844
  title: Post-transcriptional regulation of thioredoxin by the stress inducible heterogenous
    ribonucleoprotein A18.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary study showing CIRBP RRM and RGG both bind the TXN 3'-UTR, CIRBP increases TXN
      translation, interacts with eIF4G1, associates with ribosomes, and is regulated by GSK3B
      phosphorylation.
- id: PMID:16713569
  title: A protein-protein interaction network for human inherited ataxias and disorders
    of Purkinje cell degeneration.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Interaction-network screen (ATXN1 partner); supports only generic protein binding.
- id: PMID:16791210
  title: Dynamic proteomics in individual human cells uncovers widespread cell-cycle
    dependence of nuclear proteins.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: High-throughput dynamic proteomics; supports nuclear localization.
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome (HNRNPK partner); supports only generic protein binding.
- id: PMID:22365833
  title: Dynamic protein-protein interaction wiring of the human spliceosome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Spliceosome interaction map (Y2H); source of CIRBP spliceosome co-purification. Supports a
      protein interaction but not a functional splicing role; basis for marking the splicing/
      spliceosomal-complex IBA terms as over-annotated.
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Unbiased mRNA interactome capture; direct high-throughput support for RNA binding.
- id: PMID:22681889
  title: The mRNA-bound proteome and its global occupancy profile on protein-coding
    transcripts.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Independent mRNA-bound proteome; corroborates RNA binding.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale binary interactome; supports only generic protein binding.
- id: PMID:29892012
  title: An interactome perturbation framework prioritizes damaging missense mutations
    for developmental disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome (HNRNPK partner); supports only generic protein binding.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; supports only generic protein binding.
- id: PMID:32234784
  title: Nonclassical nuclear localization signals mediate nuclear import of CIRBP.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary study defining the nonclassical NLSs of CIRBP recognized by TNPO1 (RG/RGG) and
      TNPO3 (RSY); explains nuclear import and prevention of aberrant phase separation/SG
      recruitment. Makes the TNPO1/TNPO3 'protein binding' annotation functionally meaningful.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Binary interactome map; supports only generic protein binding.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Neurodegeneration interactome (ATXN1 partner); supports only generic protein binding.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cell-specific interactome (TNPO3 partner); supports only generic protein binding.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Endogenous-tagging interactome (TNPO3 partner); supports interaction and localization.
- id: PMID:9151692
  title: A glycine-rich RNA-binding protein mediating cold-inducible suppression of
    mammalian cell growth.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Founding paper: cloned mouse cirp, showed cold induction (37 to 32 C), nucleoplasmic
      localization, and an essential role in cold-induced suppression of cell growth (G1
      prolongation). Basis for the response-to-cold annotations.
- id: file:human/CIRBP/CIRBP-deep-research-falcon.md
  title: Deep research report on CIRBP (falcon/Edison), 2026-06-29
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      AI-generated literature synthesis (citing peer-reviewed reviews by Corre & Lebreton 2024,
      Rana et al. 2024, Aziz et al. 2025, Han et al. 2023, and the Zhou et al. 2025 TNPO3
      structure). Used to support stress-granule recruitment, translational repression, and the
      extracellular eCIRP/DAMP functions not present in current GOA. Underlying primary/review
      sources should be cited directly where stronger evidence is needed.