Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Cell Rep. 2022 Feb 22;38(8):110414. doi: 10.1016/j.celrep.2022.110414.
Inflammasome activation exacerbates infectious disease caused by pathogens such as Listeria monocytogenes, Staphylococcus aureus, and severe acute respiratory syndrome coronavirus 2. Although these pathogens activate host inflammasomes to regulate pathogen expansion, the mechanisms by which pathogen toxins contribute to inflammasome activation remain poorly understood. Here we show that activation of inflammasomes by Listeria infection is promoted by amino acid residue T223 of listeriolysin O (LLO) independently of its pore-forming activity. LLO T223 is critical for phosphorylation of the inflammasome adaptor ASC at amino acid residue Y144 through Lyn-Syk signaling, which is essential for ASC oligomerization. Notably, a Listeria mutant expressing LLO T223A is impaired in inducing ASC phosphorylation and inflammasome activation. Furthermore, the virulence of LLO T223A mutant is markedly attenuated in vivo due to impaired ability to activate the inflammasome. Our results reveal a function of a pathogen toxin that exacerbates infection by promoting phosphorylation of ASC.
炎症小体的激活会加剧李斯特菌、金黄色葡萄球菌和严重急性呼吸综合征冠状病毒 2 等病原体引起的传染病。尽管这些病原体激活宿主炎症小体来调节病原体的扩增，但病原体毒素促进炎症小体激活的机制仍知之甚少。在这里，我们表明李斯特菌感染通过李斯特菌溶血素 O（LLO）的氨基酸残基 T223 促进炎症小体的激活，而不依赖其孔形成活性。LLO T223 对于 Lyn-Syk 信号通路介导的 ASC 接头蛋白 Y144 上的磷酸化至关重要，这对于 ASC 寡聚化是必需的。值得注意的是，表达 LLO T223A 的李斯特菌突变体在诱导 ASC 磷酸化和炎症小体激活方面存在缺陷。此外，LLO T223A 突变体在体内的毒力明显减弱，因为其激活炎症小体的能力受损。我们的研究结果揭示了一种病原体毒素的功能，它通过促进 ASC 的磷酸化来加剧感染。
