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. Propagation Review Root cause: UNRESOLVED |
| 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, |
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Download this section (compressed HTML)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?
Q: In which direction does CC10 act on type II interferon production? The GO:0032689 IDA (PMID:15356574) asserts negative regulation, but the accessible abstract reports CC10 inducing IFN-gamma in naive CD4+ T cells. Full text is needed to establish the cell type and context, so that annotation is held as UNDECIDED.
Q: Is there any reproducible nuclear-envelope pool of CC10 (GO:0005635)? The term arrives only by electronic and ortholog transfer and is hard to reconcile with a small secreted protein; both rows are held as UNDECIDED pending direct localization evidence.
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
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