Uteroglobin (Scgb1a1; Clara/club cell 10 kDa secretory protein, CC10/CC16) is the prototypical secretoglobin: a small, secreted, disulfide-linked antiparallel homodimer with a uteroglobin fold enclosing a hydrophobic ligand cavity. It is produced and secreted by non-ciliated club cells of the airway epithelium (and other mucosal epithelia) and is strongly induced by glucocorticoids. Its best- established biochemical activity is potent inhibition of phospholipase A2, which curtails release of arachidonic acid and downstream eicosanoid/inflammatory mediators; it also binds phospholipids (phosphatidylcholine, phosphatidylinositol), hydrophobic xenobiotics such as polychlorinated biphenyls, and (weakly, with species variation) progesterone. Functionally it acts as a secreted anti- inflammatory and immunomodulatory protein, suppressing T helper 2 cytokine production (IL-4, IL-5, IL-13) in part by destabilizing GATA-3 mRNA, and damping airway inflammatory responses. It is a widely used clinical biomarker of club cell integrity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005576
extracellular region
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Uteroglobin is a classical secreted protein; localization to the extracellular region is well established and consistent across the secretoglobin family.
Reason: Secreted club cell protein; extracellular localization is core and well supported.
Supporting Evidence:
file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
Club cells (nonciliated cells of the surface
|
|
GO:0005737
cytoplasm
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: Phylogenetic inference of cytoplasmic localization, consistent with the protein being synthesized and stored in the cytoplasm/secretory granules of club cells prior to secretion.
Reason: Cytoplasmic presence reflects the biosynthetic/secretory route in the producing cell; the functional compartment is the extracellular space, so this is retained as non-core.
|
|
GO:0005576
extracellular region
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Automated localization annotation agreeing with the secreted nature of uteroglobin.
Reason: Consistent with experimentally established secretion.
|
|
GO:0007165
signal transduction
|
IEA
GO_REF:0000002 |
MARK AS OVER ANNOTATED |
Summary: Generic InterPro-based "signal transduction" annotation. This is uninformative for uteroglobin, whose documented activities are PLA2 inhibition, ligand binding and cytokine/immunomodulation rather than a defined signal-transduction role.
Reason: Overly broad, low-information term not reflecting any specific characterized signaling function of this protein.
|
|
GO:0005635
nuclear envelope
|
IEA
GO_REF:0000107 |
UNDECIDED |
Summary: Ortholog/electronically transferred nuclear envelope localization. This is biologically unexpected for a secreted club cell protein and is not supported by the primary localization data (cytoplasm of airway epithelium, secretory granules, extracellular space).
Reason: Cannot verify; inconsistent with the well-established secreted localization. Retained as UNDECIDED pending evidence rather than removed, as some reports describe receptor-mediated uptake of uteroglobin.
|
|
GO:0009410
response to xenobiotic stimulus
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Consistent with uteroglobin's documented binding/sequestration of hydrophobic xenobiotics (polychlorinated biphenyls).
Reason: Plausible and aligned with PCB binding, but electronic and non-core.
|
|
GO:0010193
response to ozone
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Electronically inferred lung response phenotype; plausible for a protective club cell protein but not a core function.
Reason: IEA phenotype-level association; non-core.
|
|
GO:0030141
secretory granule
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Consistent with storage of uteroglobin in secretory granules of club cells before regulated secretion.
Reason: Aligns with the secretory biology of this protein.
|
|
GO:0032496
response to lipopolysaccharide
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Electronically inferred response phenotype, consistent with the protein's anti-inflammatory role but not directly characterized here.
Reason: IEA; non-core.
|
|
GO:0034021
response to silicon dioxide
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Electronically inferred lung-injury response phenotype.
Reason: IEA phenotype-level association; non-core.
|
|
GO:0034097
response to cytokine
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Broad electronically inferred response; uteroglobin both responds to and modulates cytokine milieu, but this generic term is non-core.
Reason: IEA, broad; non-core.
|
|
GO:0051384
response to glucocorticoid
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Uteroglobin expression is induced by glucocorticoids, a long-established and defining regulatory feature of the gene.
Reason: Directly supported by the documented glucocorticoid induction of Scgb1a1.
Supporting Evidence:
file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
By glucocorticoids.
|
|
GO:0071774
response to fibroblast growth factor
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Electronically inferred response; not specifically characterized for uteroglobin.
Reason: IEA; non-core.
|
|
GO:0097160
polychlorinated biphenyl binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Uteroglobin binds polychlorinated biphenyls (PCBs) within its hydrophobic cavity, a documented biochemical property (the protein is also named "PCB-binding protein").
Reason: Supported by the curated biochemical function; reflects xenobiotic sequestration by the ligand cavity.
Supporting Evidence:
file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
polychlorinated biphenyls (PCB) and weakly progesterone, potent
|
|
GO:0005576
extracellular region
|
ISO
GO_REF:0000096 |
ACCEPT |
Summary: Ortholog-transferred extracellular localization, consistent with the secreted nature of uteroglobin.
Reason: Agrees with experimental secretion.
|
|
GO:0005576
extracellular region
|
ISO
GO_REF:0000119 |
ACCEPT |
Summary: Ortholog-transferred extracellular localization (mouse-human), consistent with secretion.
Reason: Agrees with experimental secretion.
|
|
GO:0005635
nuclear envelope
|
ISO
GO_REF:0000096 |
UNDECIDED |
Summary: Ortholog-transferred nuclear envelope localization; same concern as the IEA nuclear-envelope annotation.
Reason: Cannot verify; inconsistent with the established secreted localization.
|
|
GO:0030141
secretory granule
|
ISO
GO_REF:0000096 |
ACCEPT |
Summary: Ortholog-transferred secretory granule localization, consistent with regulated secretion of uteroglobin.
Reason: Aligns with the protein's secretory biology.
|
|
GO:0034097
response to cytokine
|
ISO
GO_REF:0000096 |
KEEP AS NON CORE |
Summary: Ortholog-transferred broad cytokine-response term.
Reason: Broad; non-core.
|
|
GO:0097160
polychlorinated biphenyl binding
|
ISO
GO_REF:0000096 |
ACCEPT |
Summary: Ortholog-transferred PCB binding, agreeing with the documented biochemical property.
Reason: Consistent with curated PCB-binding function.
Supporting Evidence:
file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
polychlorinated biphenyls (PCB) and weakly progesterone, potent
|
|
GO:0043488
regulation of mRNA stability
|
IDA
PMID:15356574 Regulation of TH2 responses by the pulmonary Clara cell secr... |
ACCEPT |
Summary: CC10 treatment decreased the mRNA stability of GATA-3, the master Th2 transcription factor, providing a post-transcriptional mechanism for its suppression of Th2 cytokines.
Reason: Directly demonstrated effect on GATA-3 mRNA stability.
Supporting Evidence:
PMID:15356574
stability of GATA-3 was seen in CC10-treated cells
|
|
GO:0032689
negative regulation of type II interferon production
|
IDA
PMID:15356574 Regulation of TH2 responses by the pulmonary Clara cell secr... |
UNDECIDED |
Summary: This annotation asserts that CC10 suppresses IFN-gamma (type II interferon). The cited paper's abstract instead states that CC10 suppresses Th2 cytokines but NOT IFN-gamma, and that CC10 can INDUCE IFN-gamma in naive CD4+ T cells. The negative-regulation direction therefore appears inconsistent with the cited evidence.
Reason: Apparent contradiction with the cited reference (which reports induction, not suppression, of IFN-gamma in naive T cells). Full text needed to determine the context in which any negative regulation was observed; flagged rather than removed because the curator annotated from the full text.
Supporting Evidence:
PMID:15356574
induce IFN-gamma expression in naive CD4(+) T cells
|
|
GO:0032696
negative regulation of interleukin-13 production
|
IDA
PMID:15356574 Regulation of TH2 responses by the pulmonary Clara cell secr... |
ACCEPT |
Summary: CC10 dose-dependently suppressed Th2 cytokine expression, including IL-13, in antigen-sensitized splenocytes and polarized Th2 cells.
Reason: Directly demonstrated suppression of Th2 cytokine (IL-13) production.
Supporting Evidence:
PMID:15356574
dose-dependent suppressive effect of CC10 was
|
|
GO:0032696
negative regulation of interleukin-13 production
|
IMP
PMID:15356574 Regulation of TH2 responses by the pulmonary Clara cell secr... |
ACCEPT |
Summary: In vivo reconstitution of CC10 in CC10-deficient mice lowered Th2 cytokines (including IL-13), supporting a genetic (IMP) role in suppressing IL-13.
Reason: Supported by the in vivo CC10-deficiency/reconstitution experiment.
Supporting Evidence:
PMID:15356574
dose-dependent suppressive effect of CC10 was
|
|
GO:0032713
negative regulation of interleukin-4 production
|
IDA
PMID:15356574 Regulation of TH2 responses by the pulmonary Clara cell secr... |
ACCEPT |
Summary: CC10 suppressed Th2 cytokine expression including IL-4 in sensitized splenocytes and polarized Th2 cells.
Reason: Directly demonstrated suppression of IL-4 production.
Supporting Evidence:
PMID:15356574
dose-dependent suppressive effect of CC10 was
|
|
GO:0032713
negative regulation of interleukin-4 production
|
IMP
PMID:15356574 Regulation of TH2 responses by the pulmonary Clara cell secr... |
ACCEPT |
Summary: In vivo CC10 reconstitution in CC10-deficient mice reduced Th2 cytokines including IL-4.
Reason: Supported by the in vivo deficiency/reconstitution experiment.
Supporting Evidence:
PMID:15356574
dose-dependent suppressive effect of CC10 was
|
|
GO:0032714
negative regulation of interleukin-5 production
|
IDA
PMID:15356574 Regulation of TH2 responses by the pulmonary Clara cell secr... |
ACCEPT |
Summary: CC10 suppressed Th2 cytokine expression including IL-5.
Reason: Directly demonstrated suppression of IL-5 production.
Supporting Evidence:
PMID:15356574
dose-dependent suppressive effect of CC10 was
|
|
GO:0032714
negative regulation of interleukin-5 production
|
IMP
PMID:15356574 Regulation of TH2 responses by the pulmonary Clara cell secr... |
ACCEPT |
Summary: In vivo CC10 reconstitution reduced Th2 cytokines including IL-5, with reduced pulmonary eosinophilia.
Reason: Supported by the in vivo deficiency/reconstitution experiment.
Supporting Evidence:
PMID:15356574
dose-dependent suppressive effect of CC10 was
|
|
GO:0005737
cytoplasm
|
IDA
PMID:8813084 Thyroid transcription factor-1, hepatocyte nuclear factor-3b... |
KEEP AS NON CORE |
Summary: Immunohistochemistry localized Clara cell secretory protein (CCSP/CC10) to the cytoplasm of columnar epithelial cells lining the conducting airways, consistent with its site of synthesis prior to secretion.
Reason: Reflects the biosynthetic compartment in the producing cell; the functional site of action is extracellular, so kept non-core.
Supporting Evidence:
PMID:8813084
localized to the cytoplasm of columnar
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
IDA
PMID:15356574 Regulation of TH2 responses by the pulmonary Clara cell secr... |
KEEP AS NON CORE |
Summary: CC10 reduced expression of the Th2 master transcription factor GATA-3 and Th2 cytokines. Because CC10 is a secreted protein acting via destabilization of GATA-3 mRNA, its effect on RNA Pol II transcription of cytokine genes is indirect (downstream of reduced GATA-3), not a direct transcriptional repressor activity.
Reason: The transcriptional effect is an indirect, downstream consequence of GATA-3 reduction/mRNA destabilization rather than a direct molecular function of this secreted protein; retained as non-core.
Supporting Evidence:
PMID:15356574
reduction of a critical transcription factor, GATA-3
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
IMP
PMID:15356574 Regulation of TH2 responses by the pulmonary Clara cell secr... |
KEEP AS NON CORE |
Summary: Genetic (IMP) counterpart of the indirect transcriptional effect via GATA-3 reduction.
Reason: Indirect/downstream of GATA-3 reduction; non-core.
Supporting Evidence:
PMID:15356574
reduction of a critical transcription factor, GATA-3
|
|
GO:0042130
negative regulation of T cell proliferation
|
IDA
PMID:15356574 Regulation of TH2 responses by the pulmonary Clara cell secr... |
KEEP AS NON CORE |
Summary: Consistent with CC10's direct suppressive role on T-cell-mediated inflammatory responses reported in this study.
Reason: Supported by the curated full text as part of CC10's immunomodulatory activity; kept non-core relative to the central anti-inflammatory/cytokine- suppression function.
Supporting Evidence:
PMID:15356574
dose-dependent suppressive effect of CC10 was
|
|
GO:0050727
regulation of inflammatory response
|
IDA
PMID:15356574 Regulation of TH2 responses by the pulmonary Clara cell secr... |
ACCEPT |
Summary: CC10 directly regulates T-cell-mediated inflammatory responses, dampening Th2-driven airway inflammation; this is central to uteroglobin's role as a secreted anti-inflammatory protein.
Reason: Core anti-inflammatory function, directly demonstrated.
Supporting Evidence:
PMID:15356574
dose-dependent suppressive effect of CC10 was
|
|
GO:0019834
phospholipase A2 inhibitor activity
|
IEA
file:mouse/Scgb1a1/Scgb1a1-uniprot.txt |
NEW |
Summary: NEW (proposed). Uteroglobin's defining biochemical activity is potent inhibition of phospholipase A2, the molecular basis of its anti-inflammatory effect (reduced arachidonic acid release and eicosanoid production). This curated function is absent from the current GOA molecular-function set.
Reason: Long-established, curated biochemical function of uteroglobin; provides the mechanistic molecular function underlying the accepted "regulation of inflammatory response" process annotation.
Supporting Evidence:
file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
inhibitor of phospholipase A2.
|
|
GO:0005543
phospholipid binding
|
IEA
file:mouse/Scgb1a1/Scgb1a1-uniprot.txt |
NEW |
Summary: NEW (proposed). Uteroglobin binds phospholipids (phosphatidylcholine, phosphatidylinositol) within its hydrophobic cavity; substrate/phospholipid sequestration is mechanistically linked to its phospholipase A2 inhibition. Not currently captured in GOA.
Reason: Curated biochemical property; complements the PLA2-inhibitor activity and the family's hydrophobic-ligand-binding fold.
Supporting Evidence:
file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
Binds phosphatidylcholine, phosphatidylinositol,
|
Q: What cell-surface receptor mediates the immunomodulatory effects of secreted CC10 on T cells, and how does it lead to GATA-3 mRNA destabilization?
Q: Does the phospholipase A2 inhibitor activity quantitatively account for CC10's anti-inflammatory protection in vivo, independently of its cytokine effects?
Experiment: Use proximity labeling / affinity capture with tagged recombinant CC10 on primary CD4+ T cells to identify candidate receptors, then test GATA-3 mRNA decay and Th2 cytokine output after receptor knockdown.
Hypothesis: CC10's suppression of Th2 cytokines is mediated by a specific surface receptor on CD4+ T cells acting on GATA-3 mRNA stability.
Type: receptor identification / functional assay
Experiment: Compare wild-type CC10 with PLA2-inhibition-deficient point mutants in CC10- deficient mice challenged with allergen, measuring eicosanoid levels, airway inflammation and Th2 cytokines.
Hypothesis: Phospholipase A2 inhibition is the principal driver of CC10's anti-inflammatory effect in the airway.
Type: structure-function / in vivo rescue
Prototype secretoglobin (SCGB1A1), curated as a comparator to the cat Fel d 1
secretoglobin allergen (FELCA/CH1, CH2). Uteroglobin is the family archetype.
UTER_MOUSE, gene Scgb1a1 (synonyms Cc10, Ugb, Utg).id: Q06318
gene_symbol: Scgb1a1
product_type: PROTEIN
status: DRAFT
taxon:
id: NCBITaxon:10090
label: Mus musculus
description: >-
Uteroglobin (Scgb1a1; Clara/club cell 10 kDa secretory protein, CC10/CC16) is
the prototypical secretoglobin: a small, secreted, disulfide-linked antiparallel
homodimer with a uteroglobin fold enclosing a hydrophobic ligand cavity. It is
produced and secreted by non-ciliated club cells of the airway epithelium (and
other mucosal epithelia) and is strongly induced by glucocorticoids. Its best-
established biochemical activity is potent inhibition of phospholipase A2, which
curtails release of arachidonic acid and downstream eicosanoid/inflammatory
mediators; it also binds phospholipids (phosphatidylcholine, phosphatidylinositol),
hydrophobic xenobiotics such as polychlorinated biphenyls, and (weakly, with
species variation) progesterone. Functionally it acts as a secreted anti-
inflammatory and immunomodulatory protein, suppressing T helper 2 cytokine
production (IL-4, IL-5, IL-13) in part by destabilizing GATA-3 mRNA, and damping
airway inflammatory responses. It is a widely used clinical biomarker of club
cell integrity.
existing_annotations:
- term:
id: GO:0005576
label: extracellular region
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: >-
Uteroglobin is a classical secreted protein; localization to the
extracellular region is well established and consistent across the
secretoglobin family.
action: ACCEPT
reason: Secreted club cell protein; extracellular localization is core and well supported.
supported_by:
- reference_id: file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
supporting_text: Club cells (nonciliated cells of the surface
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: >-
Phylogenetic inference of cytoplasmic localization, consistent with the
protein being synthesized and stored in the cytoplasm/secretory granules of
club cells prior to secretion.
action: KEEP_AS_NON_CORE
reason: >-
Cytoplasmic presence reflects the biosynthetic/secretory route in the
producing cell; the functional compartment is the extracellular space, so
this is retained as non-core.
- term:
id: GO:0005576
label: extracellular region
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: Automated localization annotation agreeing with the secreted nature of uteroglobin.
action: ACCEPT
reason: Consistent with experimentally established secretion.
- term:
id: GO:0007165
label: signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: >-
Generic InterPro-based "signal transduction" annotation. This is
uninformative for uteroglobin, whose documented activities are PLA2
inhibition, ligand binding and cytokine/immunomodulation rather than a
defined signal-transduction role.
action: MARK_AS_OVER_ANNOTATED
reason: >-
Overly broad, low-information term not reflecting any specific characterized
signaling function of this protein.
- term:
id: GO:0005635
label: nuclear envelope
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: located_in
review:
summary: >-
Ortholog/electronically transferred nuclear envelope localization. This is
biologically unexpected for a secreted club cell protein and is not
supported by the primary localization data (cytoplasm of airway epithelium,
secretory granules, extracellular space).
action: UNDECIDED
reason: >-
Cannot verify; inconsistent with the well-established secreted localization.
Retained as UNDECIDED pending evidence rather than removed, as some reports
describe receptor-mediated uptake of uteroglobin.
- term:
id: GO:0009410
label: response to xenobiotic stimulus
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: >-
Consistent with uteroglobin's documented binding/sequestration of
hydrophobic xenobiotics (polychlorinated biphenyls).
action: KEEP_AS_NON_CORE
reason: Plausible and aligned with PCB binding, but electronic and non-core.
- term:
id: GO:0010193
label: response to ozone
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Electronically inferred lung response phenotype; plausible for a protective club cell protein but not a core function.
action: KEEP_AS_NON_CORE
reason: IEA phenotype-level association; non-core.
- term:
id: GO:0030141
label: secretory granule
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: located_in
review:
summary: >-
Consistent with storage of uteroglobin in secretory granules of club cells
before regulated secretion.
action: ACCEPT
reason: Aligns with the secretory biology of this protein.
- term:
id: GO:0032496
label: response to lipopolysaccharide
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Electronically inferred response phenotype, consistent with the protein's anti-inflammatory role but not directly characterized here.
action: KEEP_AS_NON_CORE
reason: IEA; non-core.
- term:
id: GO:0034021
label: response to silicon dioxide
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Electronically inferred lung-injury response phenotype.
action: KEEP_AS_NON_CORE
reason: IEA phenotype-level association; non-core.
- term:
id: GO:0034097
label: response to cytokine
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Broad electronically inferred response; uteroglobin both responds to and modulates cytokine milieu, but this generic term is non-core.
action: KEEP_AS_NON_CORE
reason: IEA, broad; non-core.
- term:
id: GO:0051384
label: response to glucocorticoid
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: >-
Uteroglobin expression is induced by glucocorticoids, a long-established and
defining regulatory feature of the gene.
action: ACCEPT
reason: Directly supported by the documented glucocorticoid induction of Scgb1a1.
supported_by:
- reference_id: file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
supporting_text: By glucocorticoids.
- term:
id: GO:0071774
label: response to fibroblast growth factor
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: involved_in
review:
summary: Electronically inferred response; not specifically characterized for uteroglobin.
action: KEEP_AS_NON_CORE
reason: IEA; non-core.
- term:
id: GO:0097160
label: polychlorinated biphenyl binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: enables
review:
summary: >-
Uteroglobin binds polychlorinated biphenyls (PCBs) within its hydrophobic
cavity, a documented biochemical property (the protein is also named
"PCB-binding protein").
action: ACCEPT
reason: Supported by the curated biochemical function; reflects xenobiotic sequestration by the ligand cavity.
supported_by:
- reference_id: file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
supporting_text: polychlorinated biphenyls (PCB) and weakly progesterone, potent
- term:
id: GO:0005576
label: extracellular region
evidence_type: ISO
original_reference_id: GO_REF:0000096
qualifier: located_in
review:
summary: Ortholog-transferred extracellular localization, consistent with the secreted nature of uteroglobin.
action: ACCEPT
reason: Agrees with experimental secretion.
- term:
id: GO:0005576
label: extracellular region
evidence_type: ISO
original_reference_id: GO_REF:0000119
qualifier: located_in
review:
summary: Ortholog-transferred extracellular localization (mouse-human), consistent with secretion.
action: ACCEPT
reason: Agrees with experimental secretion.
- term:
id: GO:0005635
label: nuclear envelope
evidence_type: ISO
original_reference_id: GO_REF:0000096
qualifier: located_in
review:
summary: Ortholog-transferred nuclear envelope localization; same concern as the IEA nuclear-envelope annotation.
action: UNDECIDED
reason: Cannot verify; inconsistent with the established secreted localization.
- term:
id: GO:0030141
label: secretory granule
evidence_type: ISO
original_reference_id: GO_REF:0000096
qualifier: located_in
review:
summary: Ortholog-transferred secretory granule localization, consistent with regulated secretion of uteroglobin.
action: ACCEPT
reason: Aligns with the protein's secretory biology.
- term:
id: GO:0034097
label: response to cytokine
evidence_type: ISO
original_reference_id: GO_REF:0000096
qualifier: involved_in
review:
summary: Ortholog-transferred broad cytokine-response term.
action: KEEP_AS_NON_CORE
reason: Broad; non-core.
- term:
id: GO:0097160
label: polychlorinated biphenyl binding
evidence_type: ISO
original_reference_id: GO_REF:0000096
qualifier: enables
review:
summary: Ortholog-transferred PCB binding, agreeing with the documented biochemical property.
action: ACCEPT
reason: Consistent with curated PCB-binding function.
supported_by:
- reference_id: file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
supporting_text: polychlorinated biphenyls (PCB) and weakly progesterone, potent
- term:
id: GO:0043488
label: regulation of mRNA stability
evidence_type: IDA
original_reference_id: PMID:15356574
qualifier: acts_upstream_of_or_within
review:
summary: >-
CC10 treatment decreased the mRNA stability of GATA-3, the master Th2
transcription factor, providing a post-transcriptional mechanism for its
suppression of Th2 cytokines.
action: ACCEPT
reason: Directly demonstrated effect on GATA-3 mRNA stability.
supported_by:
- reference_id: PMID:15356574
supporting_text: stability of GATA-3 was seen in CC10-treated cells
- term:
id: GO:0032689
label: negative regulation of type II interferon production
evidence_type: IDA
original_reference_id: PMID:15356574
qualifier: acts_upstream_of_or_within
review:
summary: >-
This annotation asserts that CC10 suppresses IFN-gamma (type II interferon).
The cited paper's abstract instead states that CC10 suppresses Th2 cytokines
but NOT IFN-gamma, and that CC10 can INDUCE IFN-gamma in naive CD4+ T cells.
The negative-regulation direction therefore appears inconsistent with the
cited evidence.
action: UNDECIDED
reason: >-
Apparent contradiction with the cited reference (which reports induction, not
suppression, of IFN-gamma in naive T cells). Full text needed to determine
the context in which any negative regulation was observed; flagged rather
than removed because the curator annotated from the full text.
supported_by:
- reference_id: PMID:15356574
supporting_text: induce IFN-gamma expression in naive CD4(+) T cells
- term:
id: GO:0032696
label: negative regulation of interleukin-13 production
evidence_type: IDA
original_reference_id: PMID:15356574
qualifier: acts_upstream_of_or_within
review:
summary: >-
CC10 dose-dependently suppressed Th2 cytokine expression, including IL-13,
in antigen-sensitized splenocytes and polarized Th2 cells.
action: ACCEPT
reason: Directly demonstrated suppression of Th2 cytokine (IL-13) production.
supported_by:
- reference_id: PMID:15356574
supporting_text: dose-dependent suppressive effect of CC10 was
- term:
id: GO:0032696
label: negative regulation of interleukin-13 production
evidence_type: IMP
original_reference_id: PMID:15356574
qualifier: acts_upstream_of_or_within
review:
summary: >-
In vivo reconstitution of CC10 in CC10-deficient mice lowered Th2 cytokines
(including IL-13), supporting a genetic (IMP) role in suppressing IL-13.
action: ACCEPT
reason: Supported by the in vivo CC10-deficiency/reconstitution experiment.
supported_by:
- reference_id: PMID:15356574
supporting_text: dose-dependent suppressive effect of CC10 was
- term:
id: GO:0032713
label: negative regulation of interleukin-4 production
evidence_type: IDA
original_reference_id: PMID:15356574
qualifier: acts_upstream_of_or_within
review:
summary: CC10 suppressed Th2 cytokine expression including IL-4 in sensitized splenocytes and polarized Th2 cells.
action: ACCEPT
reason: Directly demonstrated suppression of IL-4 production.
supported_by:
- reference_id: PMID:15356574
supporting_text: dose-dependent suppressive effect of CC10 was
- term:
id: GO:0032713
label: negative regulation of interleukin-4 production
evidence_type: IMP
original_reference_id: PMID:15356574
qualifier: acts_upstream_of_or_within
review:
summary: In vivo CC10 reconstitution in CC10-deficient mice reduced Th2 cytokines including IL-4.
action: ACCEPT
reason: Supported by the in vivo deficiency/reconstitution experiment.
supported_by:
- reference_id: PMID:15356574
supporting_text: dose-dependent suppressive effect of CC10 was
- term:
id: GO:0032714
label: negative regulation of interleukin-5 production
evidence_type: IDA
original_reference_id: PMID:15356574
qualifier: acts_upstream_of_or_within
review:
summary: CC10 suppressed Th2 cytokine expression including IL-5.
action: ACCEPT
reason: Directly demonstrated suppression of IL-5 production.
supported_by:
- reference_id: PMID:15356574
supporting_text: dose-dependent suppressive effect of CC10 was
- term:
id: GO:0032714
label: negative regulation of interleukin-5 production
evidence_type: IMP
original_reference_id: PMID:15356574
qualifier: acts_upstream_of_or_within
review:
summary: In vivo CC10 reconstitution reduced Th2 cytokines including IL-5, with reduced pulmonary eosinophilia.
action: ACCEPT
reason: Supported by the in vivo deficiency/reconstitution experiment.
supported_by:
- reference_id: PMID:15356574
supporting_text: dose-dependent suppressive effect of CC10 was
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:8813084
qualifier: located_in
review:
summary: >-
Immunohistochemistry localized Clara cell secretory protein (CCSP/CC10) to
the cytoplasm of columnar epithelial cells lining the conducting airways,
consistent with its site of synthesis prior to secretion.
action: KEEP_AS_NON_CORE
reason: >-
Reflects the biosynthetic compartment in the producing cell; the functional
site of action is extracellular, so kept non-core.
supported_by:
- reference_id: PMID:8813084
supporting_text: localized to the cytoplasm of columnar
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:15356574
qualifier: acts_upstream_of_or_within
review:
summary: >-
CC10 reduced expression of the Th2 master transcription factor GATA-3 and
Th2 cytokines. Because CC10 is a secreted protein acting via destabilization
of GATA-3 mRNA, its effect on RNA Pol II transcription of cytokine genes is
indirect (downstream of reduced GATA-3), not a direct transcriptional
repressor activity.
action: KEEP_AS_NON_CORE
reason: >-
The transcriptional effect is an indirect, downstream consequence of GATA-3
reduction/mRNA destabilization rather than a direct molecular function of
this secreted protein; retained as non-core.
supported_by:
- reference_id: PMID:15356574
supporting_text: reduction of a critical transcription factor, GATA-3
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IMP
original_reference_id: PMID:15356574
qualifier: acts_upstream_of_or_within
review:
summary: Genetic (IMP) counterpart of the indirect transcriptional effect via GATA-3 reduction.
action: KEEP_AS_NON_CORE
reason: Indirect/downstream of GATA-3 reduction; non-core.
supported_by:
- reference_id: PMID:15356574
supporting_text: reduction of a critical transcription factor, GATA-3
- term:
id: GO:0042130
label: negative regulation of T cell proliferation
evidence_type: IDA
original_reference_id: PMID:15356574
qualifier: acts_upstream_of_or_within
review:
summary: >-
Consistent with CC10's direct suppressive role on T-cell-mediated
inflammatory responses reported in this study.
action: KEEP_AS_NON_CORE
reason: >-
Supported by the curated full text as part of CC10's immunomodulatory
activity; kept non-core relative to the central anti-inflammatory/cytokine-
suppression function.
supported_by:
- reference_id: PMID:15356574
supporting_text: dose-dependent suppressive effect of CC10 was
- term:
id: GO:0050727
label: regulation of inflammatory response
evidence_type: IDA
original_reference_id: PMID:15356574
qualifier: acts_upstream_of_or_within
review:
summary: >-
CC10 directly regulates T-cell-mediated inflammatory responses, dampening
Th2-driven airway inflammation; this is central to uteroglobin's role as a
secreted anti-inflammatory protein.
action: ACCEPT
reason: Core anti-inflammatory function, directly demonstrated.
supported_by:
- reference_id: PMID:15356574
supporting_text: dose-dependent suppressive effect of CC10 was
- term:
id: GO:0019834
label: phospholipase A2 inhibitor activity
evidence_type: IEA
original_reference_id: file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
qualifier: enables
review:
summary: >-
NEW (proposed). Uteroglobin's defining biochemical activity is potent
inhibition of phospholipase A2, the molecular basis of its anti-inflammatory
effect (reduced arachidonic acid release and eicosanoid production). This
curated function is absent from the current GOA molecular-function set.
action: NEW
reason: >-
Long-established, curated biochemical function of uteroglobin; provides the
mechanistic molecular function underlying the accepted "regulation of
inflammatory response" process annotation.
supported_by:
- reference_id: file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
supporting_text: inhibitor of phospholipase A2.
- term:
id: GO:0005543
label: phospholipid binding
evidence_type: IEA
original_reference_id: file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
qualifier: enables
review:
summary: >-
NEW (proposed). Uteroglobin binds phospholipids (phosphatidylcholine,
phosphatidylinositol) within its hydrophobic cavity; substrate/phospholipid
sequestration is mechanistically linked to its phospholipase A2 inhibition.
Not currently captured in GOA.
action: NEW
reason: >-
Curated biochemical property; complements the PLA2-inhibitor activity and
the family's hydrophobic-ligand-binding fold.
supported_by:
- reference_id: file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
supporting_text: Binds phosphatidylcholine, phosphatidylinositol,
core_functions:
- description: >-
Secreted phospholipase A2 inhibitor. Uteroglobin potently inhibits
phospholipase A2 activity, limiting liberation of arachidonic acid and
production of pro-inflammatory eicosanoids; this is the molecular basis of its
anti-inflammatory action in the airway lumen and other mucosal surfaces.
molecular_function:
id: GO:0019834
label: phospholipase A2 inhibitor activity
directly_involved_in:
- id: GO:0050727
label: regulation of inflammatory response
supported_by:
- reference_id: file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
supporting_text: inhibitor of phospholipase A2.
locations:
- id: GO:0005576
label: extracellular region
- description: >-
Hydrophobic-ligand binding by the uteroglobin cavity. Binds phospholipids
(phosphatidylcholine, phosphatidylinositol) and lipophilic xenobiotics
(polychlorinated biphenyls); progesterone binding is weak and of uncertain
physiological significance in mouse.
molecular_function:
id: GO:0005543
label: phospholipid binding
supported_by:
- reference_id: file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
supporting_text: Binds phosphatidylcholine, phosphatidylinositol,
locations:
- id: GO:0005576
label: extracellular region
- description: >-
Secreted immunomodulator that suppresses type 2 (Th2) airway inflammation.
CC10 dose-dependently reduces production of the Th2 cytokines IL-4, IL-5 and
IL-13, at least in part by destabilizing GATA-3 mRNA, thereby damping allergic
airway inflammation and eosinophilia.
directly_involved_in:
- id: GO:0032713
label: negative regulation of interleukin-4 production
- id: GO:0032714
label: negative regulation of interleukin-5 production
- id: GO:0032696
label: negative regulation of interleukin-13 production
- id: GO:0050727
label: regulation of inflammatory response
supported_by:
- reference_id: PMID:15356574
supporting_text: dose-dependent suppressive effect of CC10 was
- reference_id: PMID:15356574
supporting_text: stability of GATA-3 was seen in CC10-treated cells
locations:
- id: GO:0005576
label: extracellular region
knowledge_gaps:
- gap_statement: >-
The direct molecular receptor and signal-transduction route by which
secreted CC10 enters or signals to T cells to destabilize GATA-3 mRNA and
suppress Th2 cytokines is not defined.
boundary: >-
Established: CC10 suppresses Th2 cytokine production and reduces GATA-3
(via decreased GATA-3 mRNA stability). Unknown: the receptor/transduction
mechanism linking extracellular CC10 to this intracellular effect.
gap_kind:
- BIOLOGY
provenance:
- reference_id: PMID:15356574
supporting_text: reduction of a critical transcription factor, GATA-3
- gap_statement: >-
Whether progesterone/steroid binding is a physiologically relevant function
of mouse uteroglobin is doubtful.
boundary: >-
Established: mouse CC10 binds progesterone but markedly more weakly than rat
CC10 or rabbit uteroglobin. Unknown/doubtful: any physiological role for this
binding.
gap_kind:
- BIOLOGY
provenance:
- reference_id: PMID:8440203
supporting_text: casts doubt on the importance of such binding as a physiologic
proposed_new_terms: []
suggested_questions:
- question: >-
What cell-surface receptor mediates the immunomodulatory effects of secreted
CC10 on T cells, and how does it lead to GATA-3 mRNA destabilization?
experts: []
- question: >-
Does the phospholipase A2 inhibitor activity quantitatively account for CC10's
anti-inflammatory protection in vivo, independently of its cytokine effects?
experts: []
suggested_experiments:
- hypothesis: >-
CC10's suppression of Th2 cytokines is mediated by a specific surface receptor
on CD4+ T cells acting on GATA-3 mRNA stability.
description: >-
Use proximity labeling / affinity capture with tagged recombinant CC10 on
primary CD4+ T cells to identify candidate receptors, then test GATA-3 mRNA
decay and Th2 cytokine output after receptor knockdown.
experiment_type: receptor identification / functional assay
- hypothesis: >-
Phospholipase A2 inhibition is the principal driver of CC10's anti-inflammatory
effect in the airway.
description: >-
Compare wild-type CC10 with PLA2-inhibition-deficient point mutants in CC10-
deficient mice challenged with allergen, measuring eicosanoid levels, airway
inflammation and Th2 cytokines.
experiment_type: structure-function / in vivo rescue
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000096
title: Automated transfer of experimentally-verified manual GO annotation data to mouse-rat orthologs
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
findings: []
- id: GO_REF:0000119
title: Automated transfer of experimentally-verified manual GO annotation data to mouse-human orthologs
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:15356574
title: Regulation of TH2 responses by the pulmonary Clara cell secretory 10-kd protein.
findings:
- statement: >-
CC10 dose-dependently suppresses Th2 cytokine (IL-4/IL-5/IL-13) expression
and reduces GATA-3, in part by decreasing GATA-3 mRNA stability; in vivo CC10
reconstitution reduces Th2 cytokines and pulmonary eosinophilia.
supporting_text: dose-dependent suppressive effect of CC10 was
- statement: >-
CC10 does not suppress IFN-gamma and can induce IFN-gamma in naive CD4+ T
cells, complicating the "negative regulation of IFN-gamma" annotation.
supporting_text: induce IFN-gamma expression in naive CD4(+) T cells
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Abstract-only cache; primary source for the Th2-cytokine and GATA-3/mRNA
stability annotations. Abstract directly contradicts the negative-regulation-
of-IFN-gamma annotation (reports induction in naive T cells), which is flagged
UNDECIDED.
- id: PMID:8813084
title: Thyroid transcription factor-1, hepatocyte nuclear factor-3beta, surfactant protein B, C, and Clara cell secretory protein in developing mouse lung.
findings:
- statement: CCSP/CC10 localizes to the cytoplasm of columnar epithelial cells lining the conducting airways during development.
supporting_text: localized to the cytoplasm of columnar
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Abstract-only cache; supports the cytoplasmic (biosynthetic-compartment) localization in club cells.
- id: PMID:8440203
title: 'Mouse Clara cell 10-kDa (CC10) protein: cDNA nucleotide sequence and molecular basis for the variation in progesterone binding of CC10 from different species.'
findings:
- statement: >-
Mouse CC10 binds progesterone substantially more weakly than rat CC10 or
rabbit uteroglobin, casting doubt on the physiological importance of
progesterone binding.
supporting_text: casts doubt on the importance of such binding as a physiologic
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
Abstract-only cache; basis for treating progesterone/steroid binding as weak
and of doubtful physiological relevance in mouse.
- id: file:mouse/Scgb1a1/Scgb1a1-uniprot.txt
title: UniProt entry Q06318 (UTER_MOUSE), uteroglobin / Scgb1a1
findings:
- statement: >-
Uteroglobin binds phosphatidylcholine, phosphatidylinositol, polychlorinated
biphenyls and weakly progesterone, and is a potent inhibitor of phospholipase
A2; it is a secreted club cell protein induced by glucocorticoids.
supporting_text: inhibitor of phospholipase A2.
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Curated UniProt record; source for the NEW phospholipase A2 inhibitor and
phospholipid binding molecular functions, PCB binding, secretion, club cell
expression and glucocorticoid induction.