PMK-1 p38 MAPK intestinal innate immunity in Caenorhabditis elegans

In the Caenorhabditis elegans intestine, a conserved p38 MAPK cassette is the main signaling route by which infection and other physiological stresses induce antibacterial defense genes. The TIR-domain protein TIR-1, the nematode ortholog of SARM1, oligomerizes into puncta in intestinal epithelial cells under pathogen or non-pathogen stress. Its NAD+ glycohydrolase activity, which oligomerization strongly potentiates, is required to activate the cascade. TIR-1 acts upstream of the ASK1-family MAP3K NSY-1, which activates the MKK3/6-family MAP2K SEK-1, which in turn phosphorylates and activates the p38 MAPK PMK-1. PMK-1 phosphorylates the CREB/ATF bZIP transcription factor ATF-7. Unphosphorylated ATF-7 represses PMK-1-regulated genes, and phosphorylation switches it to an activator. ATF-7 occupies regulatory regions of pathogen-induced genes in a PMK-1-dependent manner and controls most genes induced by Pseudomonas aeruginosa infection. These outputs include secreted proteins such as C-type lectin domain proteins, lysozymes, CUB-like proteins and ShK-toxin-domain peptides, most of which have not been shown to act against microbes. The ShKT gene sysm-1 (T24B8.5) is the standard transcriptional reporter of pathway activity, but its only demonstrated function is as a secreted intestinal signal that promotes DNA damage-induced germ cell apoptosis. The pathway acts cell-autonomously in the intestine, cooperates with the GATA factor ELT-2, and is required for resistance to Gram-negative and Gram-positive bacteria. The same TIR-1/NSY-1/SEK-1 module also has neuronal roles in AWC asymmetry and serotonin-dependent behavior, and PMK-1 has a second transcriptional target, SKN-1, in the oxidative stress response.

Boundary. This is a concrete C. elegans module for the intestinal antibacterial arm of the p38 MAPK pathway, from TIR-1 activation to ATF-7-dependent transcription of secreted output genes. It instantiates the taxon-neutral MODULE:p38_cascade (stress input, MAP3K -> MAP2K -> p38 relay, transcriptional output). The epidermal antifungal and wound arm, in which the same cassette acts upstream of STA-2 and nlp-29, is modeled in MODULE:c_elegans_jak_independent_stat_signaling and is not repeated here. PMK-1 also phosphorylates SKN-1, which controls an oxidative-stress and detoxification program. That branch belongs to the separate SKN-1 oxidative-stress module (MODULE:nrf_oxidative_stress_response) and is only cross-referenced. The neuronal roles of TIR-1/NSY-1/SEK-1 (AWC asymmetry via UNC-43/CaMKII; serotonin and egg-laying behavior) are outside this immune boundary. Upstream inputs. TIR-1 is the only modeled activating input. Its oligomerization and NAD+ glycohydrolase activity are needed for PMK-1 phosphorylation (PMID:35098926). The TIR-1 annoton carries NAD+ nucleosidase activity, which is the activity the genetic data tie to pathway activation. The GO-CAM 568b0f9600000284 types the same node as signaling adaptor activity, the other accepted core function in the tir-1 review. How NAD+ hydrolysis by TIR-1 activates NSY-1 is unknown (see knowledge_gaps). TOL-1, the only worm Toll-like receptor, is deliberately not a member. TIR-1 activity in immunity is independent of TOL-1 (PMID:15048112), and the tol-1 review places TOL-1 in BAG-neuron signaling upstream of PMK-3, not PMK-1. The PKC-delta TPA-1 -> PKD DKF-2 input to PMK-1 and the MKP-7 ortholog VHP-1, which dephosphorylates PMK-1, are present in GO-CAM 568b0f9600000284 but have no gene reviews here. They are recorded as context, not modeled parts. Transcriptional output. Outputs are modeled as a downstream part, not as core members. The output part has two representatives with different standing. SYSM-1 (T24B8.5), a secreted ShKT-domain protein, is the standard PMK-1/ATF-7 transcriptional reporter (PMID:20369020) and is the downstream node in GO-CAM 568b0f9600000284. The sysm-1 gene review found no evidence that it is antibacterial. Its induction by P. aeruginosa is expression evidence only, single-gene RNAi of PMK-1 targets did not change pathogen susceptibility (PMID:17096597), and its only demonstrated function is as an intestine-to-germline signal required for DNA damage-induced germ cell apoptosis (PMID:35121747). It is therefore modeled as a reporter and non-immune output of the cascade, not as an antimicrobial effector. That apoptosis role is cross-referenced in MODULE:c_elegans_core_apoptosis as a systemic modulator. LYS-7 is the antimicrobial representative. Its loss increases susceptibility to several pathogens in its gene review, and its basal expression falls together with p38 pathway activity (PMID:19023415). LYS-7 is also a DAF-16 target, so it is not specific to this pathway. Two other reviewed effectors were left out on purpose. For clec-60, the cached literature (PMID:20617181) shows induction by S. aureus and other pathogens but no PMK-1 or ATF-7 dependence. The S. aureus response is largely PMK-1-independent. For lys-1, TIR-1/NSY-1-dependent expression is reported only in an abstract-only cached paper (PMID:17526726) that does not name the gene. The gene reviews put lys-1 under ELT-2 and DAF-16 control. Neither gene is given a membership claim here. Relation to surveillance immunity. ATF-7 and the PMK-1 pathway are needed to survive P. aeruginosa Exotoxin A, which inhibits translation (PMID:22520464). The ZIP-2/CEBP-2 surveillance branch that induces irg-1 and irg-2 is PMK-1-independent and is modeled in MODULE:c_elegans_translation_surveillance_immunity.