Lysosome-related organelle integrity suppresses TIR-1 aggregation to restrain toxic propagation of p38 innate immunity.

ABSTRACT: Innate immunity in bacteria, plants, and animals requires the specialized subset of Toll/interleukin-1/resistance gene (TIR) domain proteins that are nicotinamide adenine dinucleotide (NAD⁺) hydrolases. Aggregation of these TIR proteins engages their enzymatic activity, but it is unknown how this protein multimerization is regulated. Here, we discover that TIR oligomerization is controlled to prevent immune toxicity. We find that p38 propagates its own activation in a positive feedback loop, which promotes the aggregation of the lone enzymatic TIR protein in the nematode C. elegans (TIR-1, homologous to human sterile alpha and TIR motif-containing 1 [SARM1]). We perform a forward genetic screen to determine how the p38 positive feedback loop is regulated. We discover that the in

SUBMITTER: Tse-Kang SY 

PROVIDER: S-EPMC11492801 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature