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.

中文翻译：

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秀丽隐杆线虫的肠道免疫是由病原体效应子触发的保卫蛋白 TIR-1 在溶酶体相关细胞器上的聚集激活的


具有酶活性的 Toll/白细胞介素-1/耐药性 （TIR） 结构域蛋白对植物、动物和细菌的免疫至关重要。然而，目前尚不清楚这些蛋白质如何在动物的病原体感应中发挥作用。我们发现线虫秀丽隐杆线虫中的 孤酶 TIR 结构域蛋白 （TIR-1，哺乳动物不育 α 和含有 TIR 基序的 1 [SARM1] 的同源物）战略性地表达在称为溶酶体相关细胞器的特定细胞内区室的膜上。TIR-1 定位在溶酶体相关细胞器上，使线 虫秀丽隐杆线虫中的肠上皮细胞能够检查病原体效应子触发的宿主损伤。由细菌病原体铜绿假单胞菌分泌的毒力效应子碱化和浓缩溶酶体相关细胞器。这种病原体诱导的溶酶体相关细胞器的形态变化触发了 TIR-1 多聚化，它利用其内在的 NAD+ 水解酶 （NADase） 活性来激活 p38 先天免疫途径并保护宿主免受微生物中毒。因此，TIR-1 是效应子触发的免疫应答中的保护蛋白，它使肠上皮细胞能够检查病原体诱导的宿主损伤。