Pathogen infection and cholesterol deficiency activate the C. elegans p38 immune pathway through a TIR-1/SARM1 phase transition
- University of Massachusetts Chan Medical School, United States
- University of Massachusetts Medical School, United States
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.
Data availability
The mRNA-seq datasets are available from the NCBI Gene Expression Omnibus using the accession numbers GSE178572 and GSE190585.Source data files are provided for all figures.
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Sterol scarcity primes p38 immune defenses through a TIR-1/SARM1 phase transitionNCBI Gene Expression Omnibus, GSE178572.
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Transcriptional profiling of C. elegans on pathogenic Pseudomonas aeruginosaNCBI Gene Expression Omnibus, GSE119292.
Article and author information
Author details
Nicholas D Peterson
Read Pukkila-Worley
Funding
National Institute of Allergy and Infectious Diseases (R01 AI130289)
- Read Pukkila-Worley
National Institute of Allergy and Infectious Diseases (R01 AI159159)
- Read Pukkila-Worley
National Institute of Allergy and Infectious Diseases (R21 AI163430)
- Read Pukkila-Worley
Kenneth Rainin Foundation (Innovator Award)
- Read Pukkila-Worley
National Institute of Allergy and Infectious Diseases (F30 AI150127)
- Nicholas D Peterson
National Institute of Allergy and Infectious Diseases (T32 AI132152)
- Nicholas D Peterson
- Janneke D Icso
National Institute of General Medical Sciences (T32 GM107000)
- Nicholas D Peterson
National Institute of Neurological Disorders and Stroke (F31 NS122423)
- Janneke D Icso
National Institute of General Medical Sciences (R35 GM118112)
- Paul R Thompson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Peterson et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Pathogen infection and cholesterol deficiency activate the C. elegans p38 immune pathway through a TIR-1/SARM1 phase transition
eLife 11:e74206.
https://doi.org/10.7554/eLife.74206
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