Listeria Toxin Promotes Phosphorylation of the Inflammasome Adaptor ASC Through Lyn and Syk to Exacerbate Pathogen Expansion

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 was promoted by amino acid residue T223 of listeriolysin O (LLO) independently of its pore-forming activity. LLO T223 was critical for phosphorylation of the inflammasome adaptor ASC at amino acid residue Y144 through Lyn-Syk signaling, which was essential for ASC oligomerization. Notably, a Listeria mutant expressing LLO T223A was impaired in inducing ASC phosphorylation and inflammasome activation. Furthermore, the virulence of LLO T223A mutant was markedly attenuated in vivo due to impaired ability to activate the inflammasome. Our results reveal a previously unrecognized function of a pathogen toxin that exacerbates infection by promoting phosphorylation of ASC.