STA-2 is a STAT-like transcription factor that serves as a key regulator of epidermal innate immunity in C. elegans. Unlike classical STAT proteins in vertebrates, STA-2 is activated through an unconventional mechanism involving the SLC6 transporter SNF-12 rather than JAK kinases (which are absent in C. elegans). STA-2 is normally sequestered at hemidesmosomes in the epidermis, and structural damage or fungal infection triggers its release and nuclear translocation, where it activates antimicrobial peptide gene expression (particularly nlp-29). STA-2 functions downstream of the p38 MAPK (pmk-1) pathway and acts cell-autonomously in the epidermis. Additionally, STA-2 participates in ECM-to-nucleus signaling during larval development, where it works with ELT-3 to activate lysosomal V-ATPase expression at molts.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: STA-2 localizes to the cytoplasm as well as other compartments. Phylogenetic inference from STAT family members supports cytoplasmic localization. Reason: STAT proteins shuttle between cytoplasm and nucleus. STA-2 is present in cytoplasmic compartments and translocates to the nucleus upon activation. IBA annotation is appropriate for a conserved STAT family member. Supporting Evidence: file:worm/sta-2/sta-2-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0006952 defense response | IBA GO_REF:0000033 | ACCEPT | Summary: STA-2 is required for the innate immune defense response to fungal infection and wounding in the C. elegans epidermis (PMID:21575913, PMID:22470487). The phylogenetic inference is well-supported by experimental data showing sta-2 is essential for antimicrobial peptide induction. Reason: Strong experimental evidence supports this IBA annotation. Multiple publications demonstrate STA-2's role in defense response, including PMID:21575913 and PMID:22470487. Supporting Evidence: PMID:21575913 the two proteins function together to regulate AMP gene expression in the epidermis PMID:25692704 skin-penetrating infection or injury activates immune defense and antimicrobial peptide (AMP) production |
| GO:0042127 regulation of cell population proliferation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: This annotation is inferred from phylogenetic relationship to mammalian STATs which regulate cell proliferation. However, there is no experimental evidence that STA-2 regulates cell proliferation in C. elegans. The published literature focuses on its role in immunity and developmental processes (molting). Reason: While mammalian STATs are established regulators of proliferation, C. elegans STA-2 has diverged to primarily function in innate immunity and developmental ECM signaling. No experimental evidence supports a proliferation role for STA-2. This annotation may reflect ancestral STAT function but is not a characterized function of this protein. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear localization of STA-2 is well-established experimentally. STA-2 translocates to the nucleus upon activation to function as a transcription factor (PMID:21575913, PMID:31735670). Reason: IBA annotation is strongly supported by direct experimental evidence (IDA) from multiple publications confirming nuclear localization of STA-2. Supporting Evidence: PMID:21575913 the STAT transcription factor-like protein STA-2 |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: STAT proteins bind specific DNA sequences in target gene promoters. STA-2 regulates transcription of antimicrobial peptide genes like nlp-29, implying it binds to cis-regulatory regions. The STAT DNA-binding domain is conserved in STA-2. Reason: STA-2 contains a conserved STAT DNA-binding domain and functions as a transcription factor for AMP genes. Phylogenetic inference is appropriate given the functional evidence for transcriptional regulation. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: STA-2 regulates transcription of antimicrobial peptide genes (PMID:21575913, PMID:22470487) and vacuolar H+-ATPase genes (PMID:31735670). As a STAT family member, it functions as a transcriptional regulator. Reason: Well-supported by experimental evidence. STA-2 activates transcription of nlp-29 and other AMP genes, as well as V-ATPase genes during development. Supporting Evidence: PMID:21575913 the two proteins function together to regulate AMP gene expression in the epidermis PMID:31735670 mediated by the GATA transcription factor ELT-3 and the STAT family protein STA-2 |
| GO:0007259 cell surface receptor signaling pathway via JAK-STAT | IBA GO_REF:0000033 | REMOVE | Summary: This annotation is problematic because C. elegans lacks JAK kinases. While STA-2 is a STAT family member, it is activated through an unconventional mechanism involving the SLC6 transporter SNF-12 rather than JAK-mediated signaling (PMID:21575913). The title of PMID:21575913 explicitly states "Unusual regulation of a STAT protein." Reason: C. elegans does not have JAK kinases, and STA-2 is not regulated by the classical JAK-STAT pathway. This IBA annotation incorrectly transfers a mammalian signaling mechanism to a nematode protein that uses a fundamentally different activation mechanism (via SNF-12 transporter and hemidesmosomes). Supporting Evidence: PMID:21575913 These findings reveal an unorthodox mode of regulation for a STAT factor |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: STA-2 functions as a transcription factor that activates expression of target genes including antimicrobial peptides and V-ATPase genes. The STAT DNA-binding and transactivation domains are conserved. Reason: STA-2 is a bona fide transcription factor with experimental evidence for transcriptional regulation. Appropriate for STAT family member with conserved domains. Supporting Evidence: PMID:21575913 the STAT transcription factor-like protein STA-2 |
| GO:0003677 DNA binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on UniProtKB keyword mapping. STA-2 has a conserved STAT DNA-binding domain and functions as a transcription factor. Reason: Appropriate general annotation for a STAT family transcription factor with a conserved DNA-binding domain. More specific annotation (GO:0000978) is also present via IBA. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation based on InterPro domain mapping (IPR001217 STAT, IPR008967 p53-like DNA-binding domain). STA-2 contains these domains and functions as a transcription factor. Reason: Appropriate annotation based on domain architecture and functional evidence. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProtKB subcellular location. Nuclear localization is confirmed by IDA annotations from PMID:21575913 and PMID:31735670. Reason: Correct annotation, consistent with experimental evidence from multiple publications. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProtKB subcellular location. Cytoplasmic localization is expected for STAT proteins before nuclear translocation. Reason: Appropriate annotation for a STAT protein that shuttles between cytoplasm and nucleus. |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on UniProtKB keyword mapping. STA-2 is a transcription factor that activates gene expression. Reason: General annotation appropriate for a transcription factor. More specific annotations are also present. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation based on InterPro domain mapping. STA-2 regulates transcription of target genes. Reason: Appropriate annotation for a STAT transcription factor. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation based on InterPro STAT domain. STA-2 functions in signal transduction from the epidermis to the nucleus in response to infection and damage. Reason: STA-2 participates in signal transduction pathways that transmit infection and damage signals to the nucleus. Supporting Evidence: PMID:21575913 Both SNF-12 and STA-2 act cell autonomously and specifically in the epidermis to govern the transcriptional response to fungal infection |
| GO:0031982 vesicle | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProtKB subcellular location. STA-2 localization to vesicles is noted in the UniProt entry. Reason: Consistent with UniProt annotation of vesicular localization in the epidermis. |
| GO:0005634 nucleus | IDA PMID:31735670 An ECM-to-Nucleus Signaling Pathway Activates Lysosomes for ... | ACCEPT | Summary: Direct experimental evidence for nuclear localization from study of ECM-to-nucleus signaling during molting. STA-2 translocates to nucleus to activate V-ATPase gene expression. Reason: High-quality IDA annotation with clear experimental support. Supporting Evidence: PMID:31735670 mediated by the GATA transcription factor ELT-3 and the STAT family protein STA-2 |
| GO:0009611 response to wounding | IMP PMID:22470487 The pseudokinase NIPI-4 is a novel regulator of antimicrobia... | ACCEPT | Summary: sta-2 mutants fail to induce antimicrobial peptide expression upon wounding. STA-2 is required for the wound response in the epidermis (PMID:21575913, PMID:22470487). Reason: Strong experimental evidence. STA-2 is required for nlp-29 induction upon injury. Supporting Evidence: PMID:25692704 skin-penetrating infection or injury activates immune defense and antimicrobial peptide (AMP) production |
| GO:0010628 positive regulation of gene expression | IMP PMID:22470487 The pseudokinase NIPI-4 is a novel regulator of antimicrobia... | ACCEPT | Summary: STA-2 positively regulates expression of antimicrobial peptide genes (nlp-29) and other target genes. This is demonstrated by loss of gene induction in sta-2 mutants. Reason: Core function of STA-2 as a transcriptional activator is well-established. Supporting Evidence: PMID:22470487 This cascade acts upstream of the STAT-like transcription factor STA-2 |
| GO:0050832 defense response to fungus | IMP PMID:22470487 The pseudokinase NIPI-4 is a novel regulator of antimicrobia... | ACCEPT | Summary: STA-2 is required for the epidermal immune response to the fungal pathogen Drechmeria coniospora. sta-2 mutants fail to induce antimicrobial peptides upon infection (PMID:21575913, PMID:22470487). Reason: Core function of STA-2. Defense against fungal infection is a primary role of this protein in C. elegans epidermis. Supporting Evidence: PMID:21575913 Upon invasion by the fungal pathogen Drechmeria coniospora, C. elegans responds by upregulating the expression of antimicrobial peptides (AMPs) in the epidermis |
| GO:0005515 protein binding | IPI PMID:25692704 Structural damage in the C. elegans epidermis causes release... | MODIFY | Summary: STA-2 interacts with hemidesmosome components. The IPI annotation references interaction with Q21281 (likely a hemidesmosome-associated protein). This annotation is too vague. Reason: "Protein binding" is uninformative. The specific interaction context (hemidesmosome association, transporter binding) should be captured with more specific terms. STA-2 interacts with SNF-12 and is associated with hemidesmosomes. Proposed replacements: structural molecule activity Supporting Evidence: PMID:25692704 hemidesmosomes associated with a STAT-like protein, whose disruption led to detachment of STA-2 molecules from hemidesmosomes PMID:21575913 the STAT transcription factor-like protein STA-2 as a direct physical interactor of SNF-12 |
| GO:0030056 hemidesmosome | IDA PMID:25692704 Structural damage in the C. elegans epidermis causes release... | ACCEPT | Summary: Direct experimental evidence shows STA-2 localizes to hemidesmosomes in the epidermis. Structural damage to hemidesmosomes releases STA-2 to activate immune signaling (PMID:25692704). Reason: Important localization for understanding STA-2's unique activation mechanism. Hemidesmosome association is key to damage sensing. Supporting Evidence: PMID:25692704 hemidesmosomes associated with a STAT-like protein, whose disruption led to detachment of STA-2 molecules from hemidesmosomes |
| GO:0098733 hemidesmosome associated protein complex | IDA PMID:25692704 Structural damage in the C. elegans epidermis causes release... | ACCEPT | Summary: STA-2 is part of the hemidesmosome-associated protein complex in the epidermis. This is the site where STA-2 is sequestered until released by damage. Reason: Important for understanding the mechanosensory function of STA-2 in detecting epidermal damage. Supporting Evidence: PMID:25692704 hemidesmosomes associated with a STAT-like protein |
| GO:0005634 nucleus | IDA PMID:21575913 Unusual regulation of a STAT protein by an SLC6 family trans... | ACCEPT | Summary: Direct experimental evidence for nuclear localization from the foundational study of STA-2 function in epidermal immunity. Reason: High-quality experimental evidence for nuclear translocation upon activation. Supporting Evidence: PMID:21575913 the STAT transcription factor-like protein STA-2 |
| GO:0030139 endocytic vesicle | IDA PMID:21575913 Unusual regulation of a STAT protein by an SLC6 family trans... | ACCEPT | Summary: STA-2 localizes to endosome-like vesicles in the epidermis, where it may interact with SNF-12 as part of the signaling platform. Reason: Part of the unusual regulatory mechanism for STA-2. Vesicular localization is distinct from classical cytoplasmic STAT localization. Supporting Evidence: PMID:21575913 the STAT transcription factor-like protein STA-2 as a direct physical interactor of SNF-12 |
| GO:0045177 apical part of cell | IDA PMID:21575913 Unusual regulation of a STAT protein by an SLC6 family trans... | ACCEPT | Summary: STA-2 localizes to the apical region of epidermal cells, consistent with its association with hemidesmosomes at the apical epidermis-cuticle interface. Reason: Important for understanding STA-2's role in sensing cuticle damage and pathogen invasion at the apical surface. Supporting Evidence: PMID:25692704 only disturbance of the apical hemidesmosomes triggered an immune response |
| GO:0002804 positive regulation of antifungal peptide production | IMP PMID:21575913 Unusual regulation of a STAT protein by an SLC6 family trans... | ACCEPT | Summary: Core function of STA-2. sta-2 is required for induction of antimicrobial peptides (nlp-29) in response to fungal infection with Drechmeria coniospora. Reason: The most specific and appropriate annotation for STA-2's primary function in antifungal immunity. Supporting Evidence: PMID:21575913 C. elegans responds by upregulating the expression of antimicrobial peptides (AMPs) in the epidermis PMID:21575913 the two proteins function together to regulate AMP gene expression in the epidermis |
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Download this section (compressed HTML)Q: What are the specific DNA binding sites for STA-2 in the nlp-29 and other AMP gene promoters? While STA-2 is known to activate AMP gene expression, the specific cis-regulatory elements it binds have not been characterized in C. elegans.
Q: Does STA-2 interact with other transcription factors besides ELT-3? ELT-3 cooperates with STA-2 during molting, but other co-factors in the immune response may exist.
Q: What is the mechanism of STA-2 release from hemidesmosomes upon damage? The molecular details of how structural damage leads to STA-2 release and activation are not fully understood.
Experiment: ChIP-seq to identify STA-2 binding sites genome-wide. This would define the full set of STA-2 target genes and identify DNA binding motifs.
Experiment: Structure-function analysis of STA-2 domains. This would clarify which domains mediate hemidesmosome association vs nuclear translocation vs DNA binding.
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