SCGB1A1 (Secretoglobin family 1A member 1), also known as uteroglobin or club cell secretory protein (CCSP/CC10), is a small secreted homodimeric protein that functions as a multifunctional immunomodulator and anti-inflammatory agent. It is predominantly expressed in club cells (Clara cells) of the respiratory tract, where it is one of the most abundant secreted proteins in airway lining fluid. SCGB1A1 exhibits multiple protective functions including potent inhibition of phospholipase A2, sequestration of hydrophobic inflammatory mediators (prostaglandins, phospholipids, polychlorinated biphenyls), regulation of macrophage and dendritic cell function, and prevention of pathological fibronectin deposition. The protein forms an antiparallel disulfide-linked homodimer with a central hydrophobic cavity that binds diverse lipophilic ligands. Reduced SCGB1A1 levels are associated with asthma, COPD, and other inflammatory lung diseases.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | REMOVE | Summary: SCGB1A1 is a secreted protein, synthesized with an N-terminal signal peptide that directs it into the ER for secretion. While the protein transiently passes through the cytoplasm during biosynthesis, this is not its functional location. Reason: SCGB1A1 is a secreted protein that functions extracellularly in airway lining fluid, serum, and other body fluids. UniProt clearly states "Secreted" as the subcellular location. While proteins transiently occupy the cytoplasm during synthesis, this is not the functional compartment for SCGB1A1. The IBA annotation appears to be an over-annotation from phylogenetic inference that does not distinguish between transient biosynthetic localization and functional compartment. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md SCGB1A1 is synthesized with an N-terminal signal peptide that directs the nascent polypeptide into the endoplasmic reticulum for secretion. Following removal of the signal sequence, the mature protein forms homodimers in the secretory pathway before being released into the extracellular space file:human/SCGB1A1/SCGB1A1-uniprot.txt SUBCELLULAR LOCATION: Secreted. file:human/SCGB1A1/SCGB1A1-deep-research-falcon.md SCGB1A1 encodes a highly abundant, secreted airway protein (often referred to as CCSP/CC16/CC10) produced constitutively primarily by airway club cells (non-ciliated secretory epithelial cells), with protein readily detectable in airway lining fluid and also measurable in blood and urine |
| GO:0005615 extracellular space | IBA GO_REF:0000033 | ACCEPT | Summary: SCGB1A1 is abundantly secreted into extracellular space, particularly in airway lining fluid. This IBA annotation correctly captures the primary functional location of the mature protein. Reason: This annotation is strongly supported by multiple lines of evidence. SCGB1A1 is secreted by club cells and reaches extremely high concentrations in airway secretions. It is also present in serum, urine, and other body fluids. The IBA annotation is consistent with experimental data (IDA annotation from PMID:21805676) and the UniProt annotation. This represents the core functional compartment where SCGB1A1 carries out its anti-inflammatory and immunomodulatory activities. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md The protein achieves extremely high concentrations in airway secretions, representing one of the most abundant protein products of the respiratory epithelium. Beyond local secretion into airway lining fluid, SCGB1A1 is also detected in circulation, with serum and plasma levels serving as useful biomarkers PMID:21805676 Epub 2011 Sep 6. Innate immunity proteins and a new truncated form of SPLUNC1 in nasopharyngeal aspirates from infants with respiratory syncytial virus infection. file:human/SCGB1A1/SCGB1A1-uniprot.txt SUBCELLULAR LOCATION: Secreted. file:human/SCGB1A1/SCGB1A1-deep-research-falcon.md detectable in serum/plasma, sputum, bronchoalveolar lavage fluid (BALF), nasal secretions, and urine, consistent with secretion into airway lumen and translocation into the circulation |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: This is a general parent term to the more specific extracellular space annotation. While technically correct, it is less informative than GO:0005615. Reason: This IEA annotation based on UniProt subcellular location is correct but redundant with the more specific GO:0005615 (extracellular space). Since SCGB1A1 is secreted, it occupies the extracellular region. This broader term is acceptable as it provides an appropriate high-level annotation, though the more specific child term is more informative. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-uniprot.txt SUBCELLULAR LOCATION: Secreted. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: This IEA annotation based on InterPro domain is overly broad and does not capture the specific mechanism of SCGB1A1 function. SCGB1A1 modulates signaling indirectly through sequestration of ligands and inhibition of phospholipase A2, but is not itself a signaling molecule. Reason: While SCGB1A1 impacts multiple signaling pathways (NF-ΞΊB, prostaglandin signaling, inflammatory cytokine signaling), it does so through indirect mechanisms: inhibiting phospholipase A2, sequestering inflammatory mediators, and modulating immune cell function. The term "signal transduction" implies SCGB1A1 acts as a signaling molecule itself, which is not accurate. More appropriate terms would be "negative regulation of inflammatory response" or "negative regulation of signal transduction" to capture its inhibitory effects on inflammatory signaling cascades. Proposed replacements: negative regulation of inflammatory response negative regulation of signal transduction Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md One of the most extensively characterized and significant functions of SCGB1A1 is its potent inhibition of phospholipase A2 (PLA2) activity... By inhibiting secretory phospholipase A2 (sPLA2) and decreasing the level of lysophosphatidic acid, SCGB1A1 may indirectly prevent the activation of integrins PMID:10587371 Expression of uteroglobin in the human endometrium. file:human/SCGB1A1/SCGB1A1-deep-research-falcon.md CC10/SCGB1A1 suppresses Th2-type inflammation largely by modulating lung DC subsets and activation through an NF-ΞΊBβlinked pathway |
| GO:0019834 phospholipase A2 inhibitor activity | IEA GO_REF:0000043 | ACCEPT | Summary: Phospholipase A2 inhibition is one of the best-characterized and most critical molecular functions of SCGB1A1. This is a core function supported by extensive experimental evidence. Reason: This annotation captures a central molecular function of SCGB1A1. The protein is described in UniProt as a "potent inhibitor of phospholipase A2." Deep research confirms this as "one of the most extensively characterized and significant functions of SCGB1A1." The mechanism involves direct binding to PLA2 and sequestration of the calcium cofactor required for PLA2 activity. This inhibition is critical to SCGB1A1s anti-inflammatory effects, as it prevents release of arachidonic acid and subsequent production of prostaglandins, leukotrienes, and other inflammatory mediators. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md One of the most extensively characterized and significant functions of SCGB1A1 is its potent inhibition of phospholipase A2 (PLA2) activity. Phospholipase A2 catalyzes the hydrolysis of the sn-2 acyl chain from membrane phospholipids, releasing free fatty acids (particularly arachidonic acid) and lysophospholipidsβkey substrates for the generation of potent inflammatory mediators including prostaglandins, leukotrienes, and thromboxanes file:human/SCGB1A1/SCGB1A1-uniprot.txt Binds phosphatidylcholine, phosphatidylinositol, polychlorinated biphenyls (PCB) and weakly progesterone, potent inhibitor of phospholipase A2. file:human/SCGB1A1/SCGB1A1-deep-research-falcon.md Multiple sources describe SCGB1A1/CC10 as a phospholipase A2-inhibitory protein and note increased PLA2 activity in CCSP-deficient contexts |
| GO:0005515 protein binding | IPI PMID:18243143 Uteroglobin interacts with the heparin-binding site of fibro... | MODIFY | Summary: This IPI annotation documents interaction with fibronectin (FN1, P02751). While technically correct, "protein binding" is not informative about the specific function. Reason: PMID:18243143 demonstrates that SCGB1A1 binds the heparin-binding site of fibronectin and prevents fibronectin-IgA complex formation in IgA-nephropathy. This is a specific, functionally important interaction that prevents pathological matrix deposition. The generic "protein binding" term should be replaced with a more specific molecular function term that captures the biological significance of preventing fibronectin-IgA heteromerization and abnormal glomerular deposition. Proposed replacements: protease binding cell adhesion molecule binding Supporting Evidence: PMID:18243143 Uteroglobin interacts with the heparin-binding site of fibronectin and prevents fibronectin-IgA complex formation found in IgA-nephropathy... binding of Fn to uteroglobin (UG), a multifunctional anti-inflammatory protein, inhibits Fn-IgA heteromerization file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md The high-affinity binding to fibronectin represents another significant interaction, where SCGB1A1-fibronectin heteromers form to counteract both fibronectin-fibronectin and fibronectin-collagen interactions that would otherwise lead to abnormal tissue deposition file:human/SCGB1A1/SCGB1A1-deep-research-falcon.md SCGB1A1 is a major secreted club-cell product and negative regulator of lung inflammation; proposed mechanisms include IL-8 binding, VLA-4 interaction, PLA2 antagonism, and modulation of dendritic-cell/Th17 and fibronectin-IgA pathways |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | REMOVE | Summary: This is a high-throughput interactome study with TRIM32 (Q13049). Generic protein binding annotation without functional context. Reason: PMID:21516116 is a next-generation sequencing-based interactome study that uses Y2H screening - a high-throughput approach prone to false positives and detection of non-physiological interactions. No functional validation of the SCGB1A1-TRIM32 interaction is provided. Without evidence that this interaction has biological relevance to SCGB1A1 function, this annotation represents over-annotation from high-throughput data. The generic "protein binding" term adds no functional information. Supporting Evidence: PMID:21516116 Next-generation sequencing to generate interactome datasets. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput proteome-scale interactome mapping study with TRIM32. Generic annotation without functional validation. Reason: PMID:25416956 describes a proteome-scale interactome network study - high-throughput data without functional validation of individual interactions. The detection of SCGB1A1-TRIM32 interaction in this systematic screen does not provide evidence for biological relevance. Generic "protein binding" annotations from such studies should only be retained if there is supporting evidence for functional significance, which is lacking here. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: High-throughput human interactome study detecting interaction with ACTA2 (P62736). No functional validation provided. Reason: PMID:28514442 is a large-scale interactome mapping study focused on network architecture and disease networks. While it detects interaction between SCGB1A1 and ACTA2 (smooth muscle actin), there is no functional characterization or validation. Given that SCGB1A1 is a secreted protein and ACTA2 is a cytoplasmic structural protein, this interaction likely represents a false positive or artifact of the detection method. Generic "protein binding" from high-throughput screens without functional validation should be removed. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Study examining genetic variants effects on protein interactions, detecting TRIM32 interaction. High-throughput data without functional validation. Reason: PMID:31515488 examines how genetic variants disrupt protein interactions across the allele frequency spectrum. The SCGB1A1-TRIM32 interaction detected is from systematic interactome screening without functional validation. Without evidence that this interaction is biologically relevant to SCGB1A1 function, this represents over-annotation from high-throughput data. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary protein interactome reference map detecting interactions with TRIM32, AQP6 (Q13520), and TMEM43 (Q9BTV4). High-throughput data. Reason: PMID:32296183 provides a reference map of binary protein interactions from systematic screening. Multiple SCGB1A1 interactions are detected (TRIM32, AQP6, TMEM43) but without functional validation. These high-throughput detections do not provide evidence for biological relevance. The repeated detection of SCGB1A1-TRIM32 across multiple interactome studies suggests it may be a consistent artifact or represent a non-physiological interaction, as there is no mechanistic or functional literature supporting this pairing. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Interactome mapping in neurodegenerative disease detecting interactions with FOS (P01100), GATM (P50440), and HSF1 (Q00613). Context-specific high-throughput study. Reason: PMID:32814053 focuses on neurodegenerative disease protein networks and aggregation. SCGB1A1 is not a neurodegenerative disease protein, and the detected interactions with FOS, GATM, and HSF1 are not validated or contextualized for SCGB1A1 biology. These appear to be incidental detections from systematic screening in a disease context irrelevant to SCGB1A1 primary function. Generic "protein binding" annotations from such studies should be removed. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Cell-specific interactome remodeling study detecting ACTA2 interaction. High-throughput data without functional validation. Reason: PMID:33961781 examines cell-specific remodeling of the human interactome. The SCGB1A1-ACTA2 interaction is detected but not functionally validated. As noted for PMID:28514442, the interaction between secreted SCGB1A1 and cytoplasmic ACTA2 is unlikely to be physiologically relevant. Generic "protein binding" from systematic screens should be removed without supporting functional evidence. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | REMOVE | Summary: IEA annotation from orthology to mouse Scgb1a1. SCGB1A1 is a secreted protein, not a transcription factor. This annotation likely reflects indirect effects or experimental artifacts in mouse studies. Reason: SCGB1A1 is a secreted extracellular protein that lacks DNA-binding domains or nuclear localization signals. It does not function as a transcription factor. While SCGB1A1 may indirectly affect gene expression by modulating signaling pathways and immune cell function, it does not directly regulate transcription. This IEA annotation from Ensembl orthology transfer appears to be an over-annotation, possibly capturing indirect downstream effects observed in knockout or overexpression studies rather than direct molecular function of SCGB1A1. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-uniprot.txt SUBCELLULAR LOCATION: Secreted. [No nuclear localization mentioned] file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md SCGB1A1 is synthesized with an N-terminal signal peptide that directs the nascent polypeptide into the endoplasmic reticulum for secretion |
| GO:0005615 extracellular space | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate annotation with same term as IBA annotation above. This IEA version from Ensembl orthology is redundant. Reason: While this is a duplicate of the IBA annotation (line 2 of GOA file), duplicate annotations with different evidence codes are acceptable in GO. The IEA evidence from orthology corroborates the IBA phylogenetic inference, both supporting that extracellular space is the correct functional location. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-uniprot.txt SUBCELLULAR LOCATION: Secreted. |
| GO:0005635 nuclear envelope | IEA GO_REF:0000107 | REMOVE | Summary: IEA annotation from rat ortholog suggesting nuclear envelope localization. This is inconsistent with SCGB1A1 being a secreted protein and is not supported by human data. Reason: SCGB1A1 is a secreted protein with a signal peptide directing it to the ER for secretion. Nuclear envelope localization is incompatible with its established function as an extracellular anti-inflammatory protein. This IEA annotation from Ensembl orthology (based on rat P17559) appears to be a false transfer, possibly from misannotation in the rat database or detection of SCGB1A1 in nuclear envelope fractions due to contamination or non-specific associations. No experimental evidence supports nuclear envelope localization in humans. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-uniprot.txt SUBCELLULAR LOCATION: Secreted. [No nuclear envelope annotation] |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | REMOVE | Summary: Duplicate cytoplasm annotation from orthology, same issues as the IBA cytoplasm annotation reviewed above. Reason: As with the IBA cytoplasm annotation, this IEA annotation from mouse orthology does not reflect the functional compartment of SCGB1A1. The protein transiently passes through cytoplasm during biosynthesis but functions extracellularly. This is an over-annotation from orthology transfer that does not distinguish biosynthetic transit from functional location. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-uniprot.txt SUBCELLULAR LOCATION: Secreted. |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | ACCEPT | Summary: SCGB1A1 binds polychlorinated biphenyls and other xenobiotics, and club cells express high levels of xenobiotic-metabolizing enzymes. This annotation captures an important function. Reason: This annotation is well-supported. SCGB1A1 binds polychlorinated biphenyls (PCBs) and other environmental contaminants, providing a detoxification function. Club cells that produce SCGB1A1 are major sites of xenobiotic metabolism in airways, expressing high levels of cytochrome P450 enzymes. The deep research confirms SCGB1A1 contributes to xenobiotic metabolism through sequestration of lipophilic toxins. This represents a core protective function in the respiratory tract. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md Club cells, as the primary source of SCGB1A1, are also major sites of xenobiotic metabolism in the airways, and SCGB1A1 contributes to this protective function through multiple mechanisms... The ability of SCGB1A1 to bind polychlorinated biphenyls suggests another route for chemical detoxification through sequestration of lipophilic toxins file:human/SCGB1A1/SCGB1A1-uniprot.txt Binds phosphatidylcholine, phosphatidylinositol, polychlorinated biphenyls (PCB) |
| GO:0010193 response to ozone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Annotation from rat orthology. While SCGB1A1 protects against oxidative stress, specific response to ozone is a narrow environmental stimulus not well-documented for human SCGB1A1. Reason: This annotation from rat orthology reflects SCGB1A1s protective role against oxidative stress in airways. Ozone is a specific environmental oxidant pollutant, and SCGB1A1s anti-oxidative and anti-inflammatory properties would be expected to provide protection. However, this is a specific environmental exposure scenario rather than a core molecular or biological function. The annotation is acceptable as a non-core contextual function reflecting SCGB1A1s protective role in airway defense against environmental insults. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md Studies of SCGB1A1 knockout mice demonstrate that these animals develop enhanced susceptibility to oxidative challenge and exhibit exaggerated inflammatory responses following hyperoxic exposure |
| GO:0030141 secretory granule | IEA GO_REF:0000107 | ACCEPT | Summary: SCGB1A1 is stored in secretory granules within club cells before secretion. This annotation correctly captures a transient cellular compartment in the secretory pathway. Reason: This annotation is correct. SCGB1A1 is stored in characteristic dense cytoplasmic secretory granules in club cells prior to secretion, as confirmed by electron microscopy. This represents an appropriate cellular component annotation for the biosynthetic/storage compartment. Unlike the cytoplasm annotation which is too broad, secretory granule specifically identifies the pre-secretion storage compartment for this secreted protein. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md Within club cells, SCGB1A1 is stored in characteristic dense cytoplasmic secretory granules that can be visualized by transmission electron microscopy |
| GO:0032496 response to lipopolysaccharide | IEA GO_REF:0000107 | ACCEPT | Summary: SCGB1A1 modulates macrophage responses to LPS and protects against LPS-induced acute lung injury. This annotation captures an important anti-inflammatory function. Reason: This annotation is well-supported by functional studies. SCGB1A1 significantly reduces alveolar macrophage responses to LPS stimulation, blunting release of pro-inflammatory cytokines. Recombinant SCGB1A1 mitigates LPS-induced acute lung injury in mouse models. SCGB1A1-deficient mice show exaggerated inflammatory responses to LPS. This represents a core immunomodulatory function of SCGB1A1 in protecting against bacterial pathogen-associated molecular patterns. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md When alveolar macrophages are stimulated with Toll-like receptor (TLR) agonists including heat-killed Listeria monocytogenes, lipopolysaccharide (LPS), or Salmonella flagellin, recombinant SCGB1A1 protein at concentrations of 5 ΞΌg/mL significantly reduces the release of IL-1Ξ², IL-6, IL-8... In lipopolysaccharide (LPS)-induced acute lung injury models, supplementation of exogenous SCGB1A1 mitigates the increased pro-inflammatory cytokine responses |
| GO:0032689 negative regulation of type II interferon production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Annotation from mouse orthology. SCGB1A1 modulates immune responses and reduces inflammatory cytokine production, which may include effects on IFN-gamma (type II interferon). Reason: This annotation from mouse orthology reflects SCGB1A1s broad immunomodulatory effects. The deep research notes that RelA-deficient mice show similar or elevated IFN-gamma production despite SCGB1A1-expressing cells being affected, suggesting complex regulation. While SCGB1A1 likely modulates type II interferon production through its effects on dendritic cells and T cell differentiation, this is one of many immunomodulatory activities rather than a core primary function. The annotation is acceptable as a non-core immunoregulatory function. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md SCGB1A1 significantly inhibits Th17 (T helper 17) cell differentiation through modulation of dendritic cell phenotype and function... SCGB1A1 levels are highest early in life and function to inhibit Th2 (T helper 2) cell differentiation in infants file:human/SCGB1A1/SCGB1A1-deep-research-falcon.md CC10/SCGB1A1 suppresses Th2-type inflammation largely by modulating lung DC subsets and activation through an NF-ΞΊBβlinked pathway |
| GO:0032696 negative regulation of interleukin-13 production | IEA GO_REF:0000107 | ACCEPT | Summary: Annotation from mouse orthology. SCGB1A1 inhibits Th2 differentiation, which would reduce IL-13 production. This is supported by asthma literature showing IL-13 suppresses SCGB1A1. Reason: This annotation is supported by the reciprocal relationship between SCGB1A1 and IL-13. IL-13 suppresses SCGB1A1 expression in asthmatic airways, and SCGB1A1 inhibits Th2 cell differentiation which is the source of IL-13. SCGB1A1-deficient mice show increased IL-13 responses following allergen challenge. This represents an important immunomodulatory function relevant to asthma and allergic disease, where the balance between SCGB1A1 and Th2 cytokines is critical. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md Both T-helper type 2 (Th2) cytokines including IL-4 and IL-13, as well as viral infection with human rhinovirus, reduce epithelial expression of both SCGB1A1 and FOXA2... SCGB1A1 levels are highest early in life and function to inhibit Th2 (T helper 2) cell differentiation in infants file:human/SCGB1A1/SCGB1A1-uniprot.txt GO; GO:0032696; P:negative regulation of interleukin-13 production; IEA:Ensembl. file:human/SCGB1A1/SCGB1A1-deep-research-falcon.md CC10/SCGB1A1 suppresses Th2-type inflammation largely by modulating lung DC subsets and activation through an NF-ΞΊBβlinked pathway |
| GO:0032713 negative regulation of interleukin-4 production | IEA GO_REF:0000107 | ACCEPT | Summary: Similar to IL-13 annotation above, SCGB1A1 inhibits Th2 differentiation which produces IL-4. IL-4 also suppresses SCGB1A1 expression. Reason: This annotation is supported by the same evidence as IL-13 regulation. IL-4 and IL-13 are both Th2 cytokines that suppress SCGB1A1, and SCGB1A1 inhibits Th2 differentiation. The reciprocal negative regulation between SCGB1A1 and Th2 cytokines (IL-4, IL-13) is well-documented and represents an important regulatory axis in allergic and inflammatory lung disease. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md Both T-helper type 2 (Th2) cytokines including IL-4 and IL-13, as well as viral infection with human rhinovirus, reduce epithelial expression of both SCGB1A1 and FOXA2... SCGB1A1 levels are highest early in life and function to inhibit Th2 (T helper 2) cell differentiation in infants |
| GO:0032714 negative regulation of interleukin-5 production | IEA GO_REF:0000107 | ACCEPT | Summary: IL-5 is another Th2 cytokine. SCGB1A1s inhibition of Th2 differentiation would reduce IL-5 production. Reason: This annotation follows the same logic as IL-4 and IL-13 regulation. IL-5 is a Th2 cytokine that promotes eosinophil development and activation. SCGB1A1s inhibition of Th2 cell differentiation would result in decreased IL-5 production. This is particularly relevant to allergic asthma and eosinophilic inflammation, conditions where SCGB1A1 levels are reduced and IL-5-driven eosinophilia is increased. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md SCGB1A1 levels are highest early in life and function to inhibit Th2 (T helper 2) cell differentiation in infants by modulating dendritic cells |
| GO:0034021 response to silicon dioxide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Silicon dioxide (silica) exposure causes lung inflammation and fibrosis. SCGB1A1s anti-inflammatory properties would be protective, but this is a specific environmental exposure. Reason: This annotation from rat orthology reflects SCGB1A1s protective role against particulate-induced lung injury. Silica exposure causes severe inflammatory and fibrotic lung disease, and SCGB1A1s anti-inflammatory and anti-fibrotic properties would provide protection. However, this is a specific occupational/environmental exposure scenario rather than a core molecular function. The annotation is acceptable as a non-core contextual function. |
| GO:0034097 response to cytokine | IEA GO_REF:0000107 | ACCEPT | Summary: SCGB1A1 expression is regulated by cytokines (IL-13, IL-4 suppress it) and SCGB1A1 modulates cytokine production. This is a broad but accurate annotation. Reason: This annotation appropriately captures SCGB1A1s role in cytokine biology. SCGB1A1 expression is suppressed by Th2 cytokines (IL-4, IL-13) and viral infection-induced cytokines. SCGB1A1 in turn modulates production of multiple cytokines through its effects on macrophages and dendritic cells (reducing IL-1Ξ², IL-6, IL-8, TNF-Ξ±, MCP-1, and Th2 cytokines). This bidirectional relationship with cytokines is central to SCGB1A1s immunomodulatory function. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md Both T-helper type 2 (Th2) cytokines including IL-4 and IL-13, as well as viral infection with human rhinovirus, reduce epithelial expression of both SCGB1A1 and FOXA2... recombinant SCGB1A1 protein at concentrations of 5 ΞΌg/mL significantly reduces the release of IL-1Ξ², IL-6, IL-8, macrophage inflammatory protein-1Ξ± (MIP-1Ξ±), tumor necrosis factor-Ξ± (TNF-Ξ±), and monocyte chemoattractant protein-1 (MCP-1) file:human/SCGB1A1/SCGB1A1-deep-research-falcon.md Th2 cytokines can downregulate SCGB1A1 and Th1-related pathways can regulate expression via JAKβSTAT/FOXA factors |
| GO:0042130 negative regulation of T cell proliferation | IEA GO_REF:0000107 | ACCEPT | Summary: SCGB1A1 reduces lymphocyte proliferation in response to mitogenic stimulation. This is a documented immunosuppressive function. Reason: This annotation is directly supported by experimental evidence. Deep research confirms "SCGB1A1 significantly reduces lymphocyte proliferation in response to mitogenic stimulation with phytohemagglutinin (PHA), though it does not affect baseline (unstimulated) lymphocyte proliferation." This represents an important immunomodulatory function, preventing excessive T cell activation while maintaining baseline immune homeostasis. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md Recent studies reveal that SCGB1A1 significantly reduces lymphocyte proliferation in response to mitogenic stimulation with phytohemagglutinin (PHA), though it does not affect baseline (unstimulated) lymphocyte proliferation |
| GO:0043488 regulation of mRNA stability | IEA GO_REF:0000107 | REMOVE | Summary: SCGB1A1 is a secreted protein without known RNA-binding activity. This annotation likely reflects indirect effects or misannotation from mouse orthology. Reason: SCGB1A1 is a secreted extracellular protein that lacks RNA-binding domains. Direct regulation of mRNA stability requires RNA-binding activity and typically occurs in the nucleus or cytoplasm. This IEA annotation from mouse orthology appears to be an over-annotation, possibly capturing indirect downstream effects on mRNA stability of other genes rather than a direct molecular function of SCGB1A1. There is no mechanistic basis for SCGB1A1 to directly regulate mRNA stability. |
| GO:0050727 regulation of inflammatory response | IEA GO_REF:0000107 | MODIFY | Summary: This is a core function of SCGB1A1, though the term should be "negative regulation" rather than just "regulation" to accurately reflect its anti-inflammatory role. Reason: SCGB1A1 functions as an anti-inflammatory protein, not just a regulator of inflammation. The vast majority of evidence shows SCGB1A1 suppresses, inhibits, or dampens inflammatory responses through multiple mechanisms: PLA2 inhibition, cytokine sequestration, macrophage modulation, and T cell regulation. The more accurate term is "negative regulation of inflammatory response" (GO:0050728) to capture the directionality of its effect. Proposed replacements: negative regulation of inflammatory response Supporting Evidence: file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md Uteroglobin (UG), also known as Clara cell 10 kDa (CC10) protein, is the founding member of a newly recognized superfamily of proteins called Secretoglobin. It is a steroid-inducible, multifunctional, secreted protein with potent anti-inflammatory and anti-chemotactic properties file:human/SCGB1A1/SCGB1A1-deep-research-falcon.md SCGB1A1 is a major secreted club-cell product and negative regulator of lung inflammation; proposed mechanisms include IL-8 binding, VLA-4 interaction, PLA2 antagonism, and modulation of dendritic-cell/Th17 and fibronectin-IgA pathways |
| GO:0051384 response to glucocorticoid | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SCGB1A1 expression may be regulated by glucocorticoids in some contexts, but this is not well-documented in humans compared to progesterone regulation in rabbits. Reason: This annotation from rat orthology may reflect glucocorticoid regulation of SCGB1A1 expression observed in rodent models. While SCGB1A1 is described as "steroid-inducible" and progesterone regulation is well-documented in lagomorphs, direct evidence for glucocorticoid regulation in human airways is limited. However, given that glucocorticoids are therapeutic in asthma and may help restore SCGB1A1 levels, this annotation is plausible as a non-core regulatory relationship. |
| GO:0071774 response to fibroblast growth factor | IEA GO_REF:0000107 | REMOVE | Summary: Limited evidence for specific FGF response. This annotation from rat orthology is not well-supported in human SCGB1A1 literature. Reason: There is minimal evidence in the literature for SCGB1A1 regulation by or response to fibroblast growth factors. This IEA annotation from rat orthology is not supported by the deep research or UniProt annotation for human SCGB1A1. Without specific evidence for FGF interaction or regulation, this represents an unsupported orthology transfer and should be removed. |
| GO:0097160 polychlorinated biphenyl binding | IEA GO_REF:0000107 | ACCEPT | Summary: SCGB1A1 binds PCBs with high affinity through its hydrophobic cavity. This is a well-documented molecular function important for xenobiotic detoxification. Reason: This annotation is strongly supported. UniProt states SCGB1A1 "Binds phosphatidylcholine, phosphatidylinositol, polychlorinated biphenyls (PCB)." PCB binding is one of SCGB1A1s alternative names (PCB-BP). The deep research confirms "The protein also demonstrates affinity for progesterone, though this binding is relatively weak in humans compared to certain other mammalian species. Additionally, SCGB1A1 binds polychlorinated biphenyls (PCBs) and their metabolites, serving a xenobiotic detoxification function." This is a core molecular function related to environmental protection in the airways. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-uniprot.txt Binds phosphatidylcholine, phosphatidylinositol, polychlorinated biphenyls (PCB) and weakly progesterone file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md Additionally, SCGB1A1 binds polychlorinated biphenyls (PCBs) and their metabolites, serving a xenobiotic detoxification function by sequestering these probable human carcinogens and environmental contaminants |
| GO:0005515 protein binding | IPI PMID:16423471 Interaction of uteroglobin with lipocalin-1 receptor suppres... | REMOVE | Summary: This study reports interaction with lipocalin-1 receptor (LMBR1L, Q6UX01), though this finding has been disputed by later studies. Reason: PMID:16423471 reports that SCGB1A1 interacts with lipocalin-1 receptor (LMBR1L) and that this interaction suppresses cancer cell motility. However, UniProt notes "Interaction with LMBR1L has been observed in PubMed:16423471, but not in PubMed:23964685" indicating the finding has not been reproduced. Given the conflicting evidence and that the generic "protein binding" term provides no functional information, this annotation should be removed. If the LMBR1L interaction is eventually validated, a more specific functional term should be used. Supporting Evidence: file:human/SCGB1A1/SCGB1A1-uniprot.txt Interaction with LMBR1L has been observed in PubMed:16423471, but not in PubMed:23964685 PMID:16423471 Interaction of uteroglobin with lipocalin-1 receptor suppresses cancer cell motility and invasion. |
| GO:0005615 extracellular space | IDA PMID:21805676 Innate immunity proteins and a new truncated form of SPLUNC1... | ACCEPT | Summary: Direct experimental detection of SCGB1A1 in nasopharyngeal aspirates, confirming extracellular space localization. This is a third annotation for the same term with different evidence. Reason: This IDA annotation from PMID:21805676 provides direct experimental evidence for SCGB1A1 in extracellular space, specifically in nasopharyngeal aspirates from infants. This complements the IBA and IEA annotations for the same term. Multiple annotations with different evidence types for the same correct term are acceptable and strengthen confidence in the annotation. Supporting Evidence: PMID:21805676 Innate immunity proteins and a new truncated form of SPLUNC1 in nasopharyngeal aspirates from infants with respiratory syncytial virus infection... Totally, 35 proteins were identified in NPA, including several innate immunity proteins |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | ACCEPT | Summary: High-throughput detection of SCGB1A1 in exosomes from prostatic secretions. SCGB1A1 is found in various extracellular compartments including exosomes. Reason: This HDA annotation from PMID:23533145 identifies SCGB1A1 in extracellular exosomes isolated from prostatic secretions. SCGB1A1 is expressed in prostatic epithelium and its presence in exosomes is consistent with its role as a secreted protein. Recent research has explored using SCGB1A1-enriched extracellular vesicles for therapeutic delivery, confirming biological relevance of this localization. This is a valid cellular component annotation for an additional extracellular compartment. Supporting Evidence: PMID:23533145 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine file:human/SCGB1A1/SCGB1A1-deep-research-perplexity.md Recent therapeutic studies utilizing extracellular vesicle-encapsulated CC16 (sEV-CC16) have demonstrated that CC16-enriched extracellular vesicles protect mice from both LPS- and bacteria-induced acute lung injury |
| GO:0007165 signal transduction | NAS PMID:10587371 Expression of uteroglobin in the human endometrium. | MODIFY | Summary: Duplicate of the IEA signal transduction annotation reviewed earlier. Same issues apply - too broad and indirect. Reason: As discussed for the IEA signal transduction annotation, SCGB1A1 affects signaling pathways indirectly through ligand sequestration and enzyme inhibition rather than functioning as a signaling molecule itself. PMID:10587371 focuses on uteroglobin expression in endometrium and mentions signal transduction in the abstract but provides limited mechanistic detail. More appropriate terms would capture SCGB1A1s negative regulatory effects on inflammatory signaling. Proposed replacements: negative regulation of inflammatory response negative regulation of signal transduction Supporting Evidence: PMID:10587371 Uteroglobin is a progesterone binding protein, a member of the antiflammin gene family and possibly a novel cytokine |
| GO:0007565 female pregnancy | NAS PMID:10587371 Expression of uteroglobin in the human endometrium. | KEEP AS NON CORE | Summary: SCGB1A1 (uteroglobin) is expressed in the endometrium during pregnancy, particularly in the receptive phase for implantation. This is a legitimate but non-core function. Reason: SCGB1A1 was originally discovered as uteroglobin in rabbit uterus and is expressed in human endometrium with peak expression during the mid-luteal receptive phase. PMID:10587371 demonstrates this expression pattern and suggests involvement in endometrial preparations for implantation. While this is historically important and biologically valid, it represents a tissue-specific developmental role rather than the core molecular function. For SCGB1A1, the primary function is as an anti-inflammatory immunomodulator in airways, with endometrial expression being a secondary/non-core role. Supporting Evidence: PMID:10587371 Secretory uteroglobin is found in endometrial tissue homogenates in highest levels of expression during the early luteal phase... In turn, uteroglobin is released into the uterine lumen in peak amounts during the receptive phase of the menstrual cycle... These observations strongly suggest an involvement of uteroglobin in endometrial preparations for implantation |
| GO:0007566 embryo implantation | TAS PMID:10587371 Expression of uteroglobin in the human endometrium. | KEEP AS NON CORE | Summary: Similar to female pregnancy annotation, this captures SCGB1A1s role in endometrial biology and implantation. Non-core tissue-specific function. Reason: This TAS annotation is based on the same evidence as the female pregnancy annotation. PMID:10587371 shows SCGB1A1 expression peaks during the receptive phase and concludes "These observations strongly suggest an involvement of uteroglobin in endometrial preparations for implantation." While SCGB1A1 likely plays a role in creating an anti-inflammatory environment conducive to implantation, this is a specialized reproductive function rather than the core molecular function. As with female pregnancy, this should be marked as non-core. Supporting Evidence: PMID:10587371 These observations strongly suggest an involvement of uteroglobin in endometrial preparations for implantation |
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