sta-2

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.

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.

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.

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.

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 keeps the STAT DNA-binding-domain fold but not the features that make a STAT DNA-binding domain read DNA sequence. Its UniProt entry carries only the fold-level superfamilies (IPR008967, IPR012345) and lacks the STAT DNA-binding-domain signatures (Pfam PF02864, InterPro IPR013801, CDD cd14801) that its paralog STA-1, which binds DNA in ChIP-seq, carries. An independent OpenScientist analysis found that STA-2 conserves none of the three base-contacting residues of DNA-bound STAT1 (PDB 1BF5), has the most divergent DNA-binding region of the STATs compared, and lacks the activating tyrosine. Wang & Levy (2012) report no binding to a STAT consensus motif (data not shown), and no EMSA, ChIP or motif exists for STA-2. STA-2 does regulate AMP gene transcription, so the IBA is not simply wrong, but sequence-specific cis-regulatory binding is unproven and the fold alone does not establish it.

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.

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). The Taffoni & Pujol (2015) review of epidermal immunity describes STA-2 activation as acting through p38 MAPK, SNF-12 and hemidesmosomes, with no JAK step, and Wang & Levy (2012) show STA-2 (F58E6.1) is a highly divergent, nematode-specific STAT-like paralog rather than a canonical STAT.

Summary: STA-2 functions as a transcription factor that activates expression of target genes including antimicrobial peptides and V-ATPase genes. Structure-based searches detect STAT-like SH2 and DNA-binding domains in STA-2, the latter only weakly (PMID:24058748).

Reason: STA-2 is a genuine transcriptional regulator of AMP and V-ATPase genes, but GO:0000981 is a DNA-binding transcription factor activity, which by definition works through binding a specific DNA sequence. That part is unproven for STA-2 and argued against by its degenerate DNA-binding domain (see the GO:0000978 row). GO:0140110 transcription regulator activity states what the evidence shows without asserting sequence-specific DNA binding; it also fits a partner-assisted mechanism through SNF-12.

Proposed replacements: transcription regulator activity

Summary: IEA annotation based on UniProtKB keyword mapping. STA-2 has a conserved STAT DNA-binding domain and functions as a transcription factor.

Reason: STA-2 keeps the STAT DNA-binding-domain fold (AlphaFold model confident over the region) and a weak DNA-binding domain match, so some DNA contact is possible, but it lacks the STAT DNA-binding-domain signatures its paralog STA-1 has, no binding assay exists, and Wang & Levy (2012) saw no binding to a STAT motif. Neither DNA binding nor its absence is shown; ChIP or EMSA would decide it.

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: As for GO:0000981. The InterPro mapping comes from fold-level STAT and p53-like DNA-binding superfamily matches; STA-2 lacks the STAT DNA-binding-domain signature itself. Its demonstrated activity is transcriptional regulation, not sequence-specific DNA binding.

Proposed replacements: transcription regulator activity

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.

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.

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.

Summary: IEA annotation based on InterPro domain mapping. STA-2 regulates transcription of target genes.

Reason: Appropriate annotation for a STAT transcription factor.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.