Lysosomal integrity suppresses TIR-1/SARM1 aggregation to restrain toxic propagation of p38 innate immunity

Innate immunity in bacteria, plants and animals requires the specialized subset of TIR-domain proteins that are NAD+ hydrolases. Aggregation of these TIR proteins engages their enzymatic activity, but it is not known how this protein multimerization is regulated. Here, we discovered that TIR oligomerization is exquisitely controlled to prevent immune toxicity. We found that p38 propagates its own activation by promoting the feedforward expression and aggregation of the lone enzymatic TIR protein in the nematode C. elegans, TIR-1/SARM1. We performed a forward genetic screen to determine how the p38 positive feedforward loop is regulated. We discovered that the integrity of the specific lysosomal sub-compartment that expresses TIR-1/SARM1 is actively maintained to limit inappropriate aggregation of this protein and restrain toxic p38 immune activation. Thus, innate immune defenses in intestinal epithelial cells are regulated by specific control of TIR-1/SARM1 multimerization.