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| Status |
Public on Dec 16, 2021 |
| Title |
Pathogen infection and cholesterol deficiency activate the C. elegans p38 immune pathway through a TIR-1/SARM1 phase transition |
| Organism |
Caenorhabditis elegans |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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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| Overall design |
RNA-seq of uninfected C. elegans wild-type (N2) animals grown on either 0 μg/mL or 5 μg/mL cholesterol supplemented medium.
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| Contributor(s) |
Peterson ND, Pukkila-Worley R |
| Citation(s) |
35098926 |
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| Submission date |
Dec 09, 2021 |
| Last update date |
Mar 18, 2022 |
| Contact name |
Read Pukkila-Worley |
| E-mail(s) |
read.pukkila-worley@umassmed.edu
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| Organization name |
University of Massachusetts Medical School
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| Department |
Medicine
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| Lab |
Read Pukkila-Worley
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| Street address |
55 N Lake Ave
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| City |
Worcester |
| State/province |
Massachusetts |
| ZIP/Postal code |
01655 |
| Country |
USA |
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| Platforms (1) |
| GPL25145 |
BGISEQ-500 (Caenorhabditis elegans) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA787602 |
| SRA |
SRP350058 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE190585_RAW.tar |
2.9 Mb |
(http)(custom) |
TAR (of TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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