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Sterol scarcity primes p38 immune defenses through a TIR-1/SARM1 phase transition

ABSTRACT: Intracellular signaling regulators are 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 C. elegans Toll/interleukin-1 receptor domain protein (TIR-1), a homolog of the mammalian sterile alpha and TIR motif-containing 1 (SARM1), primes host immune defenses when dietary sterols are limited to handle subsequent bacterial infection. TIR-1/SARM1 is an upstream component of the p38 PMK-1 pathway in intestinal cells, an innate immune defense and stress response pathway in metazoans. Under conditions of low cholesterol availability, multimerization and precipitation of TIR-1/SARM1 potentiates the intrinsic NAD+ glycohydrolase activity of this protein complex, increases p38 PMK-1 phosphorylation, and promotes pathogen clearance from the intestine. Dietary cholesterol is required for C. elegans to survive infection with pathogenic bacteria and to support development, fecundity, and lifespan. Thus, activation of the p38 PMK-1 pathway in sterol-deficient animals is an adaptive response that allows a metazoan host to anticipate environmental threats under conditions of essential metabolite scarcity.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE178572 | GEO | 2022/03/18

REPOSITORIES: GEO

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Project description: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 for the first time 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 low cholesterol stress causes TIR-1/SARM1 to oligomerize into puncta in intestinal epithelial cells and engages its NAD+ glycohydrolase activity, which increases p38 PMK-1 phosphorylation, and primes immune effector induction in a manner that leads to reduced 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 micronutrient 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.

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Sterol scarcity primes p38 immune defenses through a TIR-1/SARM1 phase transition

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