{"doi":"10.7554/elife.74206","title":"Pathogen infection and cholesterol deficiency activate the C. elegans p38 immune pathway through a TIR-1/SARM1 phase transition","abstract":"Intracellular signaling regulators can be concentrated into membrane-free, higher ordered protein assemblies to initiate protective responses during stress — a process known as phase transition. Here, we show that a phase transition of the Caenorhabditis elegans Toll/interleukin-1 receptor domain protein (TIR-1), an NAD + glycohydrolase homologous to mammalian sterile alpha and TIR motif-containing 1 (SARM1), underlies p38 PMK-1 immune pathway activation in C. elegans intestinal epithelial cells. Through visualization of fluorescently labeled TIR-1/SARM1 protein, we demonstrate that physiologic stresses, both pathogen and non-pathogen, induce multimerization of TIR-1/SARM1 into visible puncta within intestinal epithelial cells. In vitro enzyme kinetic analyses revealed that, like mammalian SARM1, the NAD + glycohydrolase activity of C. elegans TIR-1 is dramatically potentiated by protein oligomerization and a phase transition. Accordingly, C. elegans with genetic mutations that specifically block either multimerization or the NAD + glycohydrolase activity of TIR-1/SARM1 fail to induce p38 PMK phosphorylation, are unable to increase immune effector expression, and are dramatically susceptible to bacterial infection. Finally, we demonstrate that a loss-of-function mutation in nhr-8 , which alters cholesterol metabolism and is used to study conditions of sterol deficiency, causes TIR-1/SARM1 to oligomerize into puncta in intestinal epithelial cells. Cholesterol scarcity increases p38 PMK-1 phosphorylation, primes immune effector induction in a manner that requires TIR-1/SARM1 oligomerization and its intrinsic NAD + glycohydrolase activity, and reduces pathogen accumulation in the intestine during a subsequent infection. These data reveal a new adaptive response that allows a metazoan host to anticipate pathogen threats during cholesterol deprivation, a time of relative susceptibility to infection. Thus, a phase transition of TIR-1/SARM1 as a prerequisite for its NAD + glycohydrolase activity is strongly conserved across millions of years of evolution and is essential for diverse physiological processes in multiple cell types.","journal":"eLife","year":2022,"id":235981,"datarank":1.8270898326128824,"base_score":4.304065093204169,"endowment":4.304065093204169,"self_citation_contribution":0.6456097639806255,"citation_network_contribution":1.1814800686322569,"self_endowment_contribution":0.6456097639806255,"citer_contribution":1.1814800686322569,"corpus_percentile":null,"corpus_rank":null,"citation_count":73,"citer_count":73,"citers_with_citation_signal":52,"citers_with_endowment":52,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE178572","GSE190585","GSE119292"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":855723,"name":"Janneke D Icso","orcid":null,"position":1,"is_corresponding":false},{"id":855724,"name":"J Elizabeth Salisbury","orcid":null,"position":2,"is_corresponding":false},{"id":263229,"name":"Tomás Rodríguez","orcid":"0000-0002-8724-5427","position":3,"is_corresponding":false},{"id":109690,"name":"Paul R. Thompson","orcid":"0000-0002-1621-3372","position":4,"is_corresponding":false},{"id":306040,"name":"Read Pukkila-Worley","orcid":"0000-0001-5340-8294","position":5,"is_corresponding":false},{"id":306038,"name":"Nicholas Peterson","orcid":"0000-0003-4157-8119","position":0,"is_corresponding":true}],"reference_count":99,"raw_metadata":null,"created_at":"2026-07-19T00:21:53.333008Z","pmid":"35098926","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}