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Here, we show that a phase transition of the\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    Toll\/interleukin-1 receptor domain protein (TIR-1), an NAD\n                    <jats:sup>+<\/jats:sup>\n                    glycohydrolase homologous to mammalian sterile alpha and TIR motif-containing 1 (SARM1), underlies p38 PMK-1 immune pathway activation in\n                    <jats:italic>C. elegans<\/jats:italic>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    glycohydrolase activity of\n                    <jats:italic>C. elegans<\/jats:italic>\n                    TIR-1 is dramatically potentiated by protein oligomerization and a phase transition. Accordingly,\n                    <jats:italic>C. elegans<\/jats:italic>\n                    with genetic mutations that specifically block either multimerization or the NAD\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:italic>nhr-8<\/jats:italic>\n                    , 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\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    glycohydrolase activity is strongly conserved across millions of years of evolution and is essential for diverse physiological processes in multiple cell types.\n                  <\/jats:p>","DOI":"10.7554\/elife.74206","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T08:01:54Z","timestamp":1643616114000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.74206","source":"Crossref","is-referenced-by-count":79,"title":["Pathogen infection and cholesterol deficiency activate the C. elegans p38 immune pathway through a TIR-1\/SARM1 phase transition"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4157-8119","authenticated-orcid":true,"given":"Nicholas D","family":"Peterson","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Program in Innate Immunity, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School","place":["Worcester, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janneke D","family":"Icso","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Program in Chemical Biology, University of Massachusetts Chan Medical School","place":["Worcester, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Elizabeth","family":"Salisbury","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Program in Innate Immunity, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical 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