JAK-independent STAT signaling in Caenorhabditis elegans

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.

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.