1. Immunology and Inflammation
  2. Microbiology and Infectious Disease

Pathogen infection and cholesterol deficiency activate the C. elegans p38 immune pathway through a TIR-1/SARM1 phase transition

  1. Nicholas D Peterson
  2. Janneke D Icso
  3. J. Elizabeth Salisbury
  4. Tomás Rodríguez
  5. Paul R Thompson  Is a corresponding author
  6. Read Pukkila-Worley  Is a corresponding author
  1. University of Massachusetts Chan Medical School, United States
  2. University of Massachusetts Medical School, United States
https://doi.org/10.7554/eLife.74206
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Cite this article
  1. Nicholas D Peterson
  2. Janneke D Icso
  3. J. Elizabeth Salisbury
  4. Tomás Rodríguez
  5. Paul R Thompson
  6. Read Pukkila-Worley
(2022)
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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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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Nicholas D Peterson

    Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4157-8119

  2. Janneke D Icso

    Program in Chemical Biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. J. Elizabeth Salisbury

    Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Tomás Rodríguez

    RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8724-5427

  5. Paul R Thompson

    Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    Paul.Thompson@umassmed.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1621-3372

  6. Read Pukkila-Worley

    Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, United States
    For correspondence
    read.pukkila-worley@umassmed.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5340-8294

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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  1. Nicholas D Peterson
  2. Janneke D Icso
  3. J. Elizabeth Salisbury
  4. Tomás Rodríguez
  5. Paul R Thompson
  6. Read Pukkila-Worley
(2022)
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

Share this article

https://doi.org/10.7554/eLife.74206

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