Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine; Program in Chemical Biology; Department of Biochemistry and Molecular Biotechnology; RNA Therapeutics Institute; Graduate School of Biomedical Sciences; Thompson Lab
Biochemistry | Enzymes and Coenzymes | Immunology and Infectious Disease | Medicinal-Pharmaceutical Chemistry | Microbiology
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.
TIR-1/SARM1, caenorhabditis elegans, cholesterol, immunology, infectious disease, inflammation, intestinal epithelial immunity, microbiology, p38 pathway, phase transition, pseudomonas aeruginosa
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Copyright © 2022, Peterson et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
DOI of Published Version
Peterson ND, Icso JD, Salisbury JE, Rodríguez T, Thompson PR, Pukkila-Worley R. Pathogen infection and cholesterol deficiency activate the C. elegans p38 immune pathway through a TIR-1/SARM1 phase transition. Elife. 2022 Jan 31;11:e74206. doi: 10.7554/eLife.74206. PMID: 35098926; PMCID: PMC8923663. Link to article on publisher's site
Peterson ND, Icso JD, Salisbury JE, T, Thompson PR, Pukkila-Worley R. (2022). Pathogen infection and cholesterol deficiency activate the C. elegans p38 immune pathway through a TIR-1/SARM1 phase transition. Thompson Lab Publications. https://doi.org/10.7554/eLife.74206. Retrieved from https://escholarship.umassmed.edu/thompson/119
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