Intestinal immunity in C. elegans is activated by pathogen effector-triggered aggregation of the guard protein TIR-1 on lysosome-related organelles

Toll/interleukin-1/resistance (TIR)-domain proteins with enzymatic activity are essential for immunity in plants, animals, and bacteria. However, it is not known how these proteins function in pathogen sensing in animals. We discovered that the lone enzymatic TIR-domain protein in the nematode C. elegans (TIR-1, homolog of mammalian sterile alpha and TIR motif-containing 1 [SARM1]) was strategically expressed on the membranes of a specific intracellular compartment called lysosome-related organelles. The positioning of TIR-1 on lysosome-related organelles enables intestinal epithelial cells in the nematode C. elegans to survey for pathogen effector-triggered host damage. A virulence effector secreted by the bacterial pathogen Pseudomonas aeruginosa alkalinized and condensed lysosome-related organelles. This pathogen-induced morphological change in lysosome-related organelles triggered TIR-1 multimerization, which engaged its intrinsic NAD+ hydrolase (NADase) activity to activate the p38 innate immune pathway and protect the host against microbial intoxication. Thus, TIR-1 is a guard protein in an effector-triggered immune response, which enables intestinal epithelial cells to survey for pathogen-induced host damage. [Display omitted] •C. elegans TIR-1 is expressed on the membranes of lysosome-related organelles (LROs)•Positioning of TIR-1 on LROs enables surveillance of pathogen effector-triggered damage•A pathogen-derived toxic metabolite disrupts LROs, which causes TIR-1 multimerization•TIR-1 aggregation on LROs activates the p38 innate immunity in intestinal epithelial cells TIR-domain proteins with enzymatic activity are essential for immunity across the tree of life. Tse-Kang et al. show that C. elegans TIR-1 is a guard protein in an effector-triggered immune response, which enables intestinal epithelial cells to survey for pathogen-induced host damage. These data characterize a mechanism of enzymatic TIR activation by a bacterial pathogen in animal immunity.