id: MODULE:c_elegans_jak_independent_stat_signaling title: JAK-independent STAT signaling in Caenorhabditis elegans description: >- Caenorhabditis elegans has no Janus kinase, no interferon system and no cytokine receptors that dock JAKs, yet both of its STAT-family transcription factors act in immune gene regulation. Each paralog is wired into a different upstream input and controls transcription in the opposite direction. STA-1 binds promoters in intestinal cells and acts mainly as a constitutive repressor of genes induced by Orsay virus. Its repressive function genetically requires the ACK-family non-receptor tyrosine kinase SID-3, and repression is relieved during infection. STA-2 acts in the epidermis. It is held at apical hemidesmosomes by the matrix receptor MUP-4, physically associates with the SLC6 transporter SNF-12, and is the point of convergence for a fungal-infection and wounding p38 MAPK cascade and for hemidesmosome or cuticle-collagen damage. STA-2 is required to induce antimicrobial peptide genes of the nlp-29 cluster. STA-2 lacks the conserved C-terminal phosphotyrosine motif that JAKs target in canonical STATs. status: DRAFT scope: CONCRETE evidence: - source_id: PMID:28874466 title: An Alternative STAT Signaling Pathway Acts in Viral Immunity in Caenorhabditis elegans. statement: >- C. elegans has no JAK homolog; STA-1 retains the canonical tyrosine site and acts in a JAK-independent antiviral pathway. supporting_text: >- There is no conserved homolog of the JAK kinases in C. elegans; however, the canonical tyrosine phosphorylation site on STA-1 is conserved. - source_id: PMID:28874466 title: An Alternative STAT Signaling Pathway Acts in Viral Immunity in Caenorhabditis elegans. statement: >- The two worm STAT paralogs differ in domain content: STA-2 lacks the coiled-coil domain and the tyrosine phosphorylation motif. supporting_text: >- STA-2 is similar but lacks the coiled-coil domain as well as the tyrosine phosphorylation motif - source_id: PMID:28874466 title: An Alternative STAT Signaling Pathway Acts in Viral Immunity in Caenorhabditis elegans. statement: >- The two paralogs are functionally separated in antiviral defense: loss of STA-1, but not STA-2, changes Orsay virus permissivity. supporting_text: >- sta-1 mutants were 100-fold less permissive to infection than wild-type animals, whereas sta-2 mutants showed wild-type sensitivity - source_id: PMID:34056565 title: >- ifas-1 is upregulated by fungal infection in a GPA-12 and STA-2-independent manner in the Caenorhabditis elegans epidermis. statement: >- The epidermal AMP-inducing pathways converge on STA-2. supporting_text: >- The major pathways leading to the expression of these AMP genes have been well characterized and converge on the STAT transcription factor STA-2. - source_id: PMID:24058787 title: Evolution of the JAK-STAT pathway. statement: >- Evolutionary framing: the canonical JAK-STAT pathway was assembled in Bilateria, but STAT-like proteins are older, and the nematode STATs keep an ancestral, slime-mould-like architecture. JAK-independent STAT signaling in C. elegans is therefore a lineage-specific wiring of an old transcription-factor family, not a degenerate copy of the canonical pathway. supporting_text: >- Extant members of the cnidara, the sea anemone (Nematostella vectensis) and nematode (Caenorhabditis elegans), both contain at least one STAT with architectures similar to that seen in slime mold. - source_id: PMID:24058787 title: Evolution of the JAK-STAT pathway. statement: >- Coupling of JAK, STAT, SHP and SOCS into a working pathway is a bilaterian event, the template this module is contrasted with. supporting_text: >- These came together to form the canonical JAK-STAT signaling pathway prior to the divergence of protostomia - source_id: PMID:24058748 title: Comparative evolutionary genomics of the STAT family of transcription factors. statement: >- Nematode STATs lack the N-terminal domain found in all other animal STATs, consistent with an ancestral domain structure. supporting_text: >- Prior to nematode divergence, the ancestral STAT likely had the same domain structure as the nematode STAT, lacking the N-terminal domain, which is conserved among all other known animal STATs - source_id: PMID:26716073 title: Mechanisms of innate immunity in C. elegans epidermis. statement: >- Review of C. elegans epidermal innate immunity that places STA-2 at the convergence of the p38 MAPK, SNF-12 and hemidesmosome inputs to AMP gene expression. supporting_text: >- Both the STAT family protein STA-2 and the GATA transcription factor ELT-3 are required for the transcription of nlps - source_id: file:modules/jak_stat_signaling.yaml title: Canonical JAK-STAT cytokine signaling pathway module statement: >- The canonical, taxon-neutral receptor-JAK-STAT module that this nematode module is explicitly contrasted with. - source_id: file:modules/c_elegans_jak_independent_stat_signaling-deep-research-openscientist.md title: OpenScientist module deep research statement: >- Used only for retrieval. Every claim used here was checked against cached primary papers. This led to adding PMID:16873887, PMID:18394898, PMID:33259791 and PMID:34166401. - source_id: file:genes/worm/sta-2/sta-2-ai-review.yaml title: worm sta-2 gene review statement: >- The completed sta-2 review accepts STA-2 as an epidermal transcription factor for antifungal and wound-induced AMP expression. It removes the IBA GO:0007259 JAK-STAT annotation because C. elegans lacks JAKs. - source_id: file:projects/IBA_REVIEW.md title: IBA review, section 14 (lineage-inappropriate process transfer) statement: >- Records the sta-2 GO:0007259 and gei-17 GO:0046426 IBA transfers as lineage-inappropriate. Nematodes lack the receptor-JAK-STAT pathway these terms presuppose. - source_id: file:projects/TAXON_PATHWAY_VARIANCE.md title: Taxon Pathway Variance, case study 1 statement: >- Documents JAK-STAT without JAK in C. elegans and the taxon constraints TPV-001 and TPV-002 (never in Nematoda on GO:0007259 and GO:0046425). This module was the source for TPV-001; TPV-002 came from the PTHR10782 family review and the gei-17 review. GO added both in go-ontology#32689 (2026-11-03). notes: >- Boundary. This is a concrete C. elegans module. Its theme is STAT-family transcription factors regulated without JAK kinases. It has two paralog-specific pathway variants that coexist in the same animal (selection ONE_OR_MORE) but differ in tissue, upstream input and transcriptional polarity. Each variant has its own upstream-input part and STAT transcriptional-control part. The STA-2 variant also has an effector-output part. The STA-2 epidermal pathway is the better supported of the two. It has several independent primary papers, physical interactions (SNF-12, MUP-4) and many epistasis studies. The STA-1 antiviral pathway rests on one full primary paper (PMID:28874466) and a 2026 preprint (PMID:42427644). Its upstream link from SID-3 to STA-1 is genetic only. The STA-1 variant is kept because its two parts (a non-JAK tyrosine-kinase input and a promoter-bound STAT repressor) are each directly evidenced, and because the paralog contrast is the point of the module. The knowledge gaps record its weaker grounding. The developmental role of STA-1 in dauer repression and the STA-2/ELT-3 lysosome program at the molt (PMID:31735670) are outside this immune-signaling boundary. Relation to MODULE:jak_stat_signaling. That module is a taxon-neutral receptor-JAK-STAT trunk: cytokine-receptor engagement, JAK trans-activation, receptor phosphotyrosine docking sites, STAT recruitment and tyrosine phosphorylation by JAK, dimerization and import, then GAS/ISRE transcription. Of those parts, only the last one (STAT-dependent transcription) is retained here. C. elegans has no JAK, so there is no receptor-JAK docking step and no JAK phosphorylation of STATs. No cytokine-like ligand or receptor is known for either worm pathway. The upstream inputs are an ACK-family tyrosine kinase (SID-3) for STA-1, and for STA-2 a p38 MAPK cascade plus release from a hemidesmosome receptor (MUP-4) that sequesters it. STA-1 mainly represses transcription in the basal state. Canonical STATs activate transcription after stimulation. The GO terms GO:0007259 (cell surface receptor signaling pathway via JAK-STAT) and GO:0046426 (negative regulation of cell surface receptor signaling pathway via JAK-STAT) therefore do not apply. They are deliberately absent from this module (see the sta-2 and gei-17 reviews and IBA_REVIEW section 14). GO now enforces this: GO:0007259 and GO:0046425 (the parent of GO:0046426) carry a never_in_taxon Nematoda constraint, added in go-ontology#32689 on 2026-11-03 from TPV-001 and TPV-002 in projects/TAXON_PATHWAY_VARIANCE.md, so asserting either term for a nematode protein is a constraint violation, not only a curation judgement. This module does not conform to the jak_stat_signaling template; it is a lineage-specific rewiring around a conserved STAT DNA-binding core. Other inputs and modulators. During larval molting, the astacin NAS-38 drives STA-2/SNF-12-dependent AMP expression through PMK-1 and a TGF-beta/SMA-3 branch (PMID:33259791). The collagen-damage route does not need DBL-1/SMA-6 (PMID:37759445). The SMAD branch is therefore recorded here as context, not as a separate modeled input. A D. coniospora enterotoxin can stop STA-2 from activating AMP genes, which is pathogen subversion of this pathway (PMID:34166401). Negative regulators. The canonical module's SOCS/PTP/PIAS layer has no demonstrated counterpart here. The worm PIAS GEI-17 is not shown by any cached primary paper to act on STA-1 or STA-2, so it is not modeled as a member. It is raised only as an open question (see knowledge_gaps). Family context. Both worm STATs are PANTHER PTHR11801 members. They appear among the seeds of PAINT node PTN000210448 (nucleus, regulation of transcription by RNA polymerase II) in interpro/panther/PTHR11801/PTHR11801-paint.tsv. Concrete GENE_PRODUCT selectors are used here instead of family descriptors because the module is species-scoped. Evolutionary context comes from two reviews. Liongue and Ward 2013 (PMID:24058787) date the assembly of the receptor-JAK-STAT pathway to Bilateria and note that the nematode STATs keep a slime-mould-like architecture. Wang and Levy 2012 (PMID:24058748) infer that the nematode STAT lacking the N-terminal domain reflects the ancestral domain structure. Wang and Levy also describe F58E6.1 (sta-2) as a nematode-specific duplicate of sta-1 that "can no longer be considered a bona fide member" of the STAT family and that did not bind a STAT motif in their assay. That caveat bears on the STA-2 variant's MF term. It does not change the module, because later epidermal work (PMID:21575913, PMID:37759445; reviewed in PMID:26716073) shows STA-2 is the transcriptional regulator the AMP inputs converge on. A cross-gene briefing on JAK-STAT taxon scope across the STAT, JAK and PIAS families and the C. elegans and Dictyostelium STAT modules is at https://claude.ai/artifact/4MLfbbbWWnLchDvspwdPuM. module: id: c_elegans_jak_independent_stat_signaling label: JAK-independent STAT signaling in C. elegans module_type: SIGNALING_PATHWAY description: >- Two STAT paralog-specific immune gene-regulatory pathways that operate without JAK kinases: an intestinal STA-1 antiviral repression pathway and an epidermal STA-2 antimicrobial-peptide induction pathway. concepts: - preferred_term: innate immune response term: id: GO:0045087 label: innate immune response description: >- Shared process context of both variants. The specific antiviral and antifungal/wound processes are placed on the variant nodes. context: taxa: - preferred_term: Caenorhabditis elegans term: id: NCBITaxon:6239 label: Caenorhabditis elegans cellular_components: - preferred_term: nucleus term: id: GO:0005634 label: nucleus variant_sets: - id: stat_paralog_pathways label: STAT paralog-specific JAK-independent pathways axis: STAT paralog, tissue and upstream input selection: ONE_OR_MORE notes: >- The two variants coexist in the same animal and are not alternatives for one biological step. They are grouped because each uses a STAT transcription factor without a JAK. They differ in tissue (intestine vs epidermis), upstream input (SID-3 vs p38 MAPK and hemidesmosome release) and transcriptional polarity (repression vs activation). variants: - id: sta1_antiviral label: STA-1 intestinal antiviral repression pathway module_type: SIGNALING_PATHWAY description: >- In uninfected animals STA-1 sits on chromatin near the transcription start sites of many genes. It keeps a set of Orsay virus infection-response genes repressed, and this repression genetically requires the tyrosine kinase SID-3. Infection relieves the repression and the antiviral program is induced. sta-1 and sid-3 mutants express these genes constitutively and are less permissive to the virus. The STA-1 pathway acts in parallel to antiviral RNAi. concepts: - preferred_term: negative regulation of defense response to virus term: id: GO:0050687 label: negative regulation of defense response to virus description: >- In the basal state STA-1 restrains the antiviral gene-expression program. - preferred_term: antiviral innate immune response term: id: GO:0140374 label: antiviral innate immune response description: >- The response that is derepressed when STA-1 repression is relieved during Orsay virus infection. context: anatomical_locations: - preferred_term: intestine description: >- WBbt:0005772 intestine. Orsay virus infects intestinal cells, and GFP::STA-1 accumulates on chromatin in intestinal nuclei. The WBbt id is given in text because the WBbt prefix is not configured for label validation. conditions: - preferred_term: Orsay virus infection evidence: - source_id: PMID:28874466 title: An Alternative STAT Signaling Pathway Acts in Viral Immunity in Caenorhabditis elegans. statement: >- Model in which SID-3 maintains STA-1 repression in uninfected animals and infection curtails it. supporting_text: >- We propose a model (Fig. 7) whereby in uninfected animals, SID-3 is required to maintain repression of viral infection response genes by STA-1. Upon infection, this signaling is curtailed, inducing an antiviral response program. parts: - order: 1 role: non-JAK tyrosine kinase input required for STA-1 repression node: id: sid3_input label: SID-3 tyrosine kinase input to STA-1 module_type: REGULATORY_STEP description: >- SID-3 is an ACK-family non-receptor tyrosine kinase that is also needed for systemic RNAi. Its role here comes from an RNAi screen of 116 kinases for Orsay virus load, in which sid-3 was the only hit. sid-3 mutants derepress largely the same infection-response genes as sta-1 mutants, and those genes are enriched for STA-1 ChIP-seq binding. That places SID-3 genetically upstream of STA-1. Direct phosphorylation of STA-1 by SID-3 has not been shown. annotons: - id: sid3_kinase label: SID-3 non-receptor tyrosine kinase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SID-3 term: id: UniProtKB:Q10925 label: Tyrosine-protein kinase sid-3 function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity description: >- The catalytic activity is established for SID-3 in dsRNA import (the kinase-dead K139A mutant fails to rescue). Its substrate in the antiviral pathway is unknown. processes: - preferred_term: negative regulation of defense response to virus term: id: GO:0050687 label: negative regulation of defense response to virus locations: - preferred_term: cytoplasm term: id: GO:0005737 label: cytoplasm role_description: >- Genetically upstream, non-JAK kinase input needed to keep STA-1-dependent repression of antiviral genes in place. evidence: - source_id: PMID:28874466 title: An Alternative STAT Signaling Pathway Acts in Viral Immunity in Caenorhabditis elegans. statement: >- sid-3 and sta-1 mutants derepress overlapping STA-1-bound genes, placing SID-3 upstream of STA-1. supporting_text: >- Moreover, genes upregulated in sid-3 mutants, including those shared with sta-1, were enriched for STA-1 binding by ChIP-seq, suggesting that sid-3 acts upstream of sta-1 in the antiviral gene expression response - source_id: PMID:22912399 title: Conserved tyrosine kinase promotes the import of silencing RNA into Caenorhabditis elegans cells. statement: SID-3 belongs to the ACK family of cytoplasmic tyrosine kinases. supporting_text: >- C. elegans contains two members of this broadly conserved family of tyrosine kinases: SID-3 and Ack related kinase-1 (ARK-1). - source_id: PMID:28874467 title: An Evolutionarily Conserved Pathway Essential for Orsay Virus Infection of Caenorhabditis elegans. statement: >- SID-3 is a non-receptor tyrosine kinase that is separately required at an early, pre-replication stage of Orsay virus infection. supporting_text: >- we demonstrated that both genes affect an early prereplication stage of Orsay virus infection - order: 2 role: STAT promoter binding and transcriptional repression node: id: sta1_repression label: STA-1 repression of antiviral response genes module_type: MOLECULAR_FUNCTION description: >- STA-1 binds about 20% of promoters, about 200 bp upstream of the transcription start site, at an ISRE/STAT-like motif and also at GATA-like motif sites. It is needed to keep infection-induced genes repressed in uninfected animals. Preprint evidence (PMID:42427644) indicates that repression needs STA-1 nuclear localization, its DNA-binding residues and its conserved C-terminal tyrosine (Y588). STA-1 leaves the nuclei of infected cells. annotons: - id: sta1_repressor label: STA-1 DNA-binding transcriptional repressor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: STA-1 term: id: UniProtKB:Q9NAD6 label: Signal transducer and activator of transcription 1 function: preferred_term: DNA-binding transcription repressor activity, RNA polymerase II-specific term: id: GO:0001227 label: DNA-binding transcription repressor activity, RNA polymerase II-specific targets: - preferred_term: Orsay virus infection-response gene promoters (e.g. sdz-6 reporter, dod-21, dod-23, dct-17) processes: - preferred_term: negative regulation of transcription by RNA polymerase II term: id: GO:0000122 label: negative regulation of transcription by RNA polymerase II - preferred_term: negative regulation of defense response to virus term: id: GO:0050687 label: negative regulation of defense response to virus locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- Promoter-bound STAT that mainly represses the antiviral gene-expression program in the basal state. This is the opposite polarity to canonical STATs, which activate transcription when stimulated. evidence: - source_id: PMID:28874466 title: An Alternative STAT Signaling Pathway Acts in Viral Immunity in Caenorhabditis elegans. statement: STA-1 largely acts as a transcriptional repressor of the antiviral program. supporting_text: >- These data suggest that STA-1 largely acts as a transcriptional repressor of an antiviral gene expression program. - source_id: PMID:28874466 title: An Alternative STAT Signaling Pathway Acts in Viral Immunity in Caenorhabditis elegans. statement: GFP::STA-1 ChIP-seq shows genome-wide promoter binding. supporting_text: >- Through GFP::STA-1 ChIP-seq, we identified 2,133 STA-1 peaks across the genome. - source_id: PMID:28874466 title: An Alternative STAT Signaling Pathway Acts in Viral Immunity in Caenorhabditis elegans. statement: STA-1 is nuclear and chromatin-associated in intestinal cells. supporting_text: >- accumulated on chromatin in the nuclei of intestinal cells - source_id: PMID:16873887 title: "C. elegans STAT: evolution of a regulatory switch." statement: >- STA-1 recognizes a phylogenetically conserved STAT cis element but lacks the N-terminal oligomerization domain of other STATs. supporting_text: >- recognizing a cis DNA element conserved through phylogeny. Unexpectedly, STA-1 lacks the conserved amino-terminal oligomerization domain found in vertebrate and other invertebrate STAT proteins - source_id: PMID:42427644 title: >- Viral infection drives cell-intrinsic re-localization of the C. elegans immune-repressive STAT transcription factor STA-1. statement: >- Preprint: STA-1 leaves the nuclei of infected cells but stays nuclear in uninfected cells, so it acts cell-intrinsically. supporting_text: >- C. elegans STA-1 protein disappears from nuclei of cells infected with the natural viral pathogen, Orsay virus, but remains nuclear in uninfected cells connections: - source: sid3_input target: sta1_repression connection_type: POSITIVELY_REGULATES description: >- SID-3 is genetically required for STA-1-dependent repression. Whether this is direct phosphorylation of STA-1 or an indirect effect is unresolved. evidence: - source_id: PMID:28874466 title: An Alternative STAT Signaling Pathway Acts in Viral Immunity in Caenorhabditis elegans. statement: The mechanism of the SID-3 to STA-1 link is explicitly unresolved. supporting_text: >- Whether the phosphorylation is directly mediated by a signaling cascade downstream of the kinase activity of SID-3 or conversely is caused by disruption of the SID-3 complex upon infection (as would potentially be mimicked by the sid-3 mutation) is still a point of discussion. - id: sta2_epidermal label: STA-2 epidermal antimicrobial peptide pathway module_type: SIGNALING_PATHWAY description: >- Fungal infection by Drechmeria coniospora, needle wounding and damage to apical hemidesmosomes or specific cuticle collagens all induce antimicrobial peptide (AMP) genes in the epidermis (hyp7 syncytium). Two inputs converge on STA-2. The first is a GPCR (DCAR-1), G-protein, PKC-delta (TPA-1), TIR-1 and p38 MAPK (NSY-1/SEK-1/PMK-1) cascade that acts genetically upstream of STA-2 and of its vesicular partner SNF-12. The second is release of STA-2 from the hemidesmosome receptor MUP-4 when the cuticle-hemidesmosome link is disrupted, which bypasses the p38 cascade. STA-2 then drives AMP gene expression cell-autonomously. concepts: - preferred_term: antifungal innate immune response term: id: GO:0061760 label: antifungal innate immune response - preferred_term: response to wounding term: id: GO:0009611 label: response to wounding - preferred_term: positive regulation of antifungal peptide production term: id: GO:0002804 label: positive regulation of antifungal peptide production context: anatomical_locations: - preferred_term: hypodermis description: >- WBbt:0005733 hypodermis (epidermis). SNF-12 and STA-2 act cell-autonomously in the epidermis. The WBbt id is given in text because the WBbt prefix is not configured for label validation. conditions: - preferred_term: Drechmeria coniospora infection - preferred_term: epidermal wounding or hemidesmosome/cuticle-collagen damage gocam_associations: - model: gomodel:5b91dbd100002057 title: Antifungal innate immune response in the hypodermis via MAPK cascade (C. elegans) description: >- This GO-CAM models the upstream cascade from NIPI-3, GPA-12, RACK-1, PLC and TPA-1 through PMK-1 to nlp-29. It does not include STA-2, SNF-12 or MUP-4, so the STAT node is a candidate addition to that model. evidence: - source_id: PMID:21575913 title: Unusual regulation of a STAT protein by an SLC6 family transporter in C. elegans epidermal innate immunity. statement: SNF-12 and STA-2 act together, cell-autonomously in the epidermis, to regulate AMP genes. supporting_text: >- Both SNF-12 and STA-2 act cell autonomously and specifically in the epidermis to govern the transcriptional response to fungal infection. - source_id: PMID:29487136 title: >- A Damage Sensor Associated with the Cuticle Coordinates Three Core Environmental Stress Responses in Caenorhabditis elegans. statement: >- STA-2 is needed for nlp-29 induction by infection and wounding but not by high NaCl, which shows that the STA-2 input is stimulus-specific. supporting_text: >- nlp-29 also depends on the STAT transcription factor-like protein STA-2 during infection and wounding, but not high NaCl - source_id: PMID:26716073 title: Mechanisms of innate immunity in C. elegans epidermis. statement: >- Review: STA-2, together with the GATA factor ELT-3, is required for epidermal nlp AMP gene transcription downstream of the TIR-1/p38 MAPK pathway. supporting_text: >- Both the STAT family protein STA-2 and the GATA transcription factor ELT-3 are required for the transcription of nlps parts: - order: 1 role: upstream inputs converging on STA-2 node: id: sta2_upstream_inputs label: p38 MAPK and hemidesmosome inputs to STA-2 module_type: REGULATORY_STEP description: >- Two genetically separable inputs converge on STA-2. The p38 MAPK cascade carries infection and wounding signals. Release of STA-2 from the hemidesmosome receptor MUP-4 signals structural damage and does not need DCAR-1, TIR-1, SEK-1 or PMK-1. annotons: - id: pmk1_p38_input label: PMK-1 p38 MAPK input participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PMK-1 term: id: UniProtKB:Q17446 label: Mitogen-activated protein kinase pmk-1 function: preferred_term: MAP kinase activity term: id: GO:0004707 label: MAP kinase activity processes: - preferred_term: antifungal innate immune response term: id: GO:0061760 label: antifungal innate immune response role_description: >- Terminal kinase of the epidermal DCAR-1/TPA-1/TIR-1/NSY-1/SEK-1 cascade, genetically upstream of STA-2. Its direct substrate in this pathway is unknown, and STA-2 has no demonstrated phosphorylation. gocam_associations: - model: gomodel:5b91dbd100002057 activity: gomodel:5b91dbd100002057/5b91dbd100002097 title: Antifungal innate immune response in the hypodermis via MAPK cascade (C. elegans) evidence: - source_id: PMID:22470487 title: The pseudokinase NIPI-4 is a novel regulator of antimicrobial peptide gene expression. statement: >- The PKC-delta/TIR-1/p38 MAPK cassette acts upstream of STA-2, which binds the C terminus of SNF-12. supporting_text: >- This cascade acts upstream of the STAT-like transcription factor STA-2 that physically interacts with the C-terminus of the SLC6 transporter SNF-12 - source_id: PMID:18394898 title: Distinct innate immune responses to infection and wounding in the C. elegans epidermis. statement: >- The epidermal p38 MAPK cascade is required for nlp-29 induction by both infection and wounding. supporting_text: >- We find that a conserved p38-MAP kinase cascade is required in the epidermis for the response to both infection and wounding. - source_id: PMID:33259791 title: Innate Immunity Promotes Sleep through Epidermal Antimicrobial Peptides. statement: >- During molting, NAS-38 activates the PMK-1 and TGF-beta/SMA-3 pathways, which cause STA-2- and SNF-12-dependent AMP expression. supporting_text: >- activate p38 mitogen-activated protein (MAP)/PMK-1 kinase and transforming growth factor - source_id: PMID:25086774 title: >- Activation of a G protein-coupled receptor by its endogenous ligand triggers the innate immune response of Caenorhabditis elegans. statement: The cascade is initiated by the GPCR DCAR-1. supporting_text: >- Through a functional genomic screen, we identified a single GPCR, DCAR-1, as being required for the expression of antimicrobial peptides - id: mup4_sta2_sequestration label: MUP-4 hemidesmosomal sequestration of STA-2 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MUP-4 term: id: UniProtKB:Q21281 label: Transmembrane matrix receptor MUP-4 function: preferred_term: protein sequestering activity term: id: GO:0140311 label: protein sequestering activity targets: - preferred_term: STA-2 locations: - preferred_term: hemidesmosome term: id: GO:0030056 label: hemidesmosome role_description: >- Apical hemidesmosome receptor that links the epidermis to the cuticle (BLI-1 is a presumptive, not biochemically confirmed, cuticle ligand) and holds STA-2. When the cuticle-receptor link is broken by damage, STA-2 is released to induce AMPs. This damage-sensing input bypasses the p38 cascade. evidence: - source_id: PMID:37759445 title: C. elegans Hemidesmosomes Sense Collagen Damage to Trigger Innate Immune Response in the Epidermis. statement: MUP-4 binds and sequesters STA-2 and releases it on apical structural damage. supporting_text: >- MUP-4 exerts immune surveillance function through binding and sequestering STA-2 under normal conditions and releasing STA-2 to induce AMPs upon apical structural damage - source_id: PMID:37759445 title: C. elegans Hemidesmosomes Sense Collagen Damage to Trigger Innate Immune Response in the Epidermis. statement: >- The AMP response to collagen damage needs STA-2 but not DCAR-1, TIR-1, SEK-1, PMK-1, the TGF-beta pathway, WNK-1 or ELT-3. supporting_text: >- Only the loss of STA-2 blocked the elevation of AMP transcription caused by dpy-7 inactivation - source_id: PMID:25692704 title: Structural damage in the C. elegans epidermis causes release of STA-2 and induction of an innate immune response. statement: Hemidesmosome disruption detaches STA-2 and induces AMP transcription. supporting_text: >- The epidermis recognized structural damage through hemidesmosomes associated with a STAT-like protein, whose disruption led to detachment of STA-2 molecules from hemidesmosomes and transcription of AMPs. - source_id: PMID:26716073 title: Mechanisms of innate immunity in C. elegans epidermis. statement: >- Review: STA-2 binds the apical hemidesmosome component MUP-4, and severe injury can induce AMPs independently of p38 but through STA-2. supporting_text: >- STA-2 physically interacts with one apical component of CeHDs, MUP-4 a transmembrane multidomain protein - source_id: PMID:26716073 title: Mechanisms of innate immunity in C. elegans epidermis. statement: >- Review: the damage route bypasses the p38 MAPK cascade but still needs STA-2. supporting_text: >- upregulation of nlp-29 and cnc-2 could occur in a p38 independent, but STA-2 dependent way - order: 2 role: STAT-dependent transcriptional activation of AMP genes node: id: sta2_transcription label: STA-2/SNF-12-dependent activation of AMP genes module_type: MOLECULAR_FUNCTION description: >- STA-2 acts with its physical partner SNF-12, an SLC6 transporter on epidermal endosome-like vesicles, to induce the nlp-29 cluster (nlp-27 to nlp-34) and related AMP genes. The cis-elements STA-2 binds have not been defined. annotons: - id: sta2_transcription_factor label: STA-2 transcriptional regulator participant: selector_type: GENE_PRODUCT gene_product: preferred_term: STA-2 term: id: UniProtKB:Q20977 label: Signal transducer and activator of transcription b function: preferred_term: transcription regulator activity term: id: GO:0140110 label: transcription regulator activity description: >- Acts as an activator of AMP genes. Transcription regulator activity rather than DNA-binding transcription factor activity, following the sta-2 gene review: STA-2 keeps the STAT DNA-binding-domain fold but lacks the STAT DNA-binding-domain signature (Pfam PF02864) that STA-1 has, conserves none of the STAT1 base-contacting residues, and has never been shown to bind DNA. It may reach promoters through partners such as SNF-12. targets: - preferred_term: nlp-29 cluster AMP gene promoters processes: - preferred_term: positive regulation of antifungal peptide production term: id: GO:0002804 label: positive regulation of antifungal peptide production - preferred_term: response to wounding term: id: GO:0009611 label: response to wounding locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus - preferred_term: hemidesmosome term: id: GO:0030056 label: hemidesmosome description: Pre-activation reservoir, held by MUP-4. role_description: >- The STAT that the epidermal AMP-inducing inputs converge on. It lacks the phosphotyrosine motif that JAKs target in canonical STATs. evidence: - source_id: PMID:21575913 title: Unusual regulation of a STAT protein by an SLC6 family transporter in C. elegans epidermal innate immunity. statement: STA-2 binds SNF-12 directly and the two regulate AMP gene expression together. supporting_text: >- We also identify the STAT transcription factor-like protein STA-2 as a direct physical interactor of SNF-12 and show that the two proteins function together to regulate AMP gene expression in the epidermis. - source_id: PMID:29487136 title: >- A Damage Sensor Associated with the Cuticle Coordinates Three Core Environmental Stress Responses in Caenorhabditis elegans. statement: STA-2 is fully required for the epidermal antimicrobial response to furrow-collagen loss. supporting_text: >- Conversely, sta-2 is completely required and elt-3 is partially required for the antimicrobial response in the epidermis - source_id: PMID:24058748 title: Comparative evolutionary genomics of the STAT family of transcription factors. statement: >- Caveat for the MF term: STA-2 (F58E6.1) did not bind a STAT consensus motif in a heterologous assay, which is why the generic MF term is used and direct promoter binding is not asserted. supporting_text: >- co-expression of F58E6.1 with a tyrosine kinase in mammalian tissue culture system failed to show any DNA binding activities using a STAT consensus DNA sequence motif - id: snf12_sta2_partner label: SNF-12 vesicular partner of STA-2 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SNF-12 term: id: UniProtKB:O45813 label: Sodium-dependent transporter snf-12 function: preferred_term: STAT family protein binding term: id: GO:0097677 label: STAT family protein binding processes: - preferred_term: positive regulation of antifungal peptide production term: id: GO:0002804 label: positive regulation of antifungal peptide production role_description: >- SLC6 transporter that binds STA-2 through its C terminus and is needed for AMP induction. It is proposed to act as a signaling platform on endosome-like vesicles. Its function here is STA-2 binding, as in its gene review; no transport substrate is known. evidence: - source_id: PMID:22470487 title: The pseudokinase NIPI-4 is a novel regulator of antimicrobial peptide gene expression. statement: SNF-12 localizes to epidermal endosome-like vesicles and may be a signaling platform. supporting_text: >- SNF-12 is found in endosome-like vesicles in the epidermis, where it may act as a signaling platform during the innate immune response. - source_id: PMID:26716073 title: Mechanisms of innate immunity in C. elegans epidermis. statement: >- Review: SNF-12 binds STA-2 and the two colocalize in dynamin-dependent endocytic vesicles. supporting_text: >- SNF-12 physically interacts with the transcription factor STA-2 and they have been found to colocalise in dyn-1-dependent-endocytic vesicles - order: 3 role: antimicrobial peptide effector output node: id: amp_output label: nlp-29 cluster antimicrobial peptide output module_type: BIOLOGICAL_PROCESS description: >- Secreted NLP/YARP antimicrobial peptides whose genes STA-2 induces in the epidermis. They are the effector output of the pathway. annotons: - id: nlp29_effector label: NLP-29 antimicrobial peptide participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NLP-29 term: id: UniProtKB:O44664 label: Neuropeptide-like protein 29 processes: - preferred_term: defense response to fungus term: id: GO:0050832 label: defense response to fungus locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Infection- and wound-induced secreted peptide; the readout of STA-2 activity. No molecular function is asserted because direct microbicidal activity of mature NLP-29 has not been shown (see the nlp-29 review). gocam_associations: - model: gomodel:5b91dbd100002057 activity: gomodel:5b91dbd100002057/5c4605cc00004174 title: Antifungal innate immune response in the hypodermis via MAPK cascade (C. elegans) connections: - source: pmk1_p38_input target: sta2_transcription connection_type: POSITIVELY_REGULATES description: >- The p38 MAPK cascade acts genetically upstream of STA-2/SNF-12. The molecular link is unknown. - source: mup4_sta2_sequestration target: sta2_transcription connection_type: NEGATIVELY_REGULATES description: >- MUP-4 holds STA-2 at hemidesmosomes. Damage releases it, which derepresses AMP induction. - source: sta2_transcription target: amp_output connection_type: CAUSES description: STA-2-dependent transcription induces nlp-29 cluster AMP genes. knowledge_gaps: - gap_statement: >- The kinase that acts on STA-1, and the biochemical basis of the link from SID-3 to STA-1, are unknown. No direct SID-3-STA-1 interaction or SID-3-dependent STA-1 phosphorylation has been shown. boundary: >- Genetic placement of SID-3 upstream of STA-1 rests on overlapping derepressed gene sets and ChIP enrichment. SID-3 is also required separately for an early pre-replication step of Orsay virus infection (viral entry). The low viral load in sid-3 mutants therefore does not by itself show that SID-3 signals to STA-1. gap_kind: - BIOLOGY status: OPEN significance: >- Determines whether the STA-1 variant is a true kinase-to-STAT signaling relay or two parallel requirements for viral permissivity. resolution: >- Test SID-3 phosphorylation of STA-1 Y588 in vitro and in vivo, and STA-1 phosphorylation and nuclear retention in sid-3 kinase-dead animals. provenance: - reference_id: PMID:42427644 supporting_text: >- C. elegans lacks homologs to mammalian JAK tyrosine kinases and it is not clear which kinase performs analogous functions in phosphorylating STA-1. - gap_statement: >- How STA-2 is activated downstream of the p38 MAPK cascade and SNF-12 is unknown. No STA-2 post-translational modification or PMK-1 substrate link has been reported. STA-2 binding sites in AMP gene promoters have not been mapped. boundary: >- Epistasis places the TPA-1/TIR-1/p38 cassette upstream of STA-2, and STA-2 binds SNF-12 and MUP-4. The step between these inputs and STA-2 transcriptional activity is not characterized. gap_kind: - BIOLOGY status: OPEN significance: >- This is the central mechanistic difference from canonical STAT activation by tyrosine phosphorylation, and it remains unexplained. resolution: >- Phosphoproteomics of STA-2 after infection, STA-2 ChIP-seq in infected and wounded epidermis, and structure-function mapping of the SNF-12 and MUP-4 binding surfaces. provenance: - reference_id: PMID:21575913 supporting_text: >- These findings reveal an unorthodox mode of regulation for a STAT factor - reference_id: PMID:26716073 supporting_text: >- It is still not clear how p38 MAPK-dependent STA-2 activation and trafficking are regulated in C. elegans epidermis. - gap_statement: >- It is not known whether the PIAS SUMO ligase GEI-17, or any SOCS-, phosphatase- or PIAS-type negative regulator, acts on STA-1 or STA-2. boundary: >- GEI-17 is the only worm PIAS. Its GO:0046426 IBA (negative regulation of cell surface receptor signaling pathway via JAK-STAT) is a lineage-inappropriate transfer, now also excluded by GO's never-in-Nematoda constraint on GO:0046425. No cached primary paper shows GEI-17 acting on either worm STAT, so the canonical negative-regulation layer is left out of this module. gap_kind: - BIOLOGY status: OPEN significance: >- Whether worm STATs keep the conserved PIAS-STAT interaction even though JAK signaling was lost. resolution: >- Test GEI-17 binding to and SUMOylation of STA-1 and STA-2, and test the effect of gei-17 loss on STA-1 target derepression and nlp-29 induction. provenance: - reference_id: PMID:28874466 supporting_text: >- despite the fact that both upstream and downstream genes in the pathway are not conserved in mammals and C. elegans - gap_statement: >- Preprint evidence suggests that the RIG-I-like sensor DRH-1 interacts with STA-1 in cytoplasmic puncta during infection and may restrain it. Peer-reviewed confirmation and the functional significance are lacking. gap_kind: - BIOLOGY status: OPEN significance: >- Would supply the missing infection-sensing input that relieves STA-1 repression. resolution: >- Peer-reviewed replication; test whether drh-1 loss blocks STA-1 nuclear exit and target derepression in infected cells. provenance: - reference_id: PMID:42427644 supporting_text: >- During viral infection, STA-1 forms cytoplasmic puncta that interact with the RNA viral sensor DRH-1, suggesting that DRH-1 helps restrain this immune-repressive factor.