[W9] Workshop 9
Selected from Oral Session 4: Pathogenicity (Cell invasion, Proliferation, Paracitism and Immune Evasion) and Biophylaxis

[W9-5/ODP-151] LLO promotes phosphorylation of the inflammasome adaptor ASC through Lyn to exacerbate infection

Yuko Tanishita¹, Hisateru Sekiya¹, Gabriel Nunez², Akihiko Yoshimura¹, Hideki Hara¹ (¹Dept. Microbiol. Immunol., Sch. Med., Keio Univ., ²Dept. Pathol., Sch. Med., Univ. Mich.)

Activation of inflammasome, an intracellular sensing system against microbial components, exacerbates infectious disease caused by pathogens such as Listeria monocytogenes and Staphylococcus aureus. 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 LLO (listeriolysin O) independently of its pore-forming activity. LLO T223 was critical for phosphorylation of the inflammasome adaptor ASC (apoptosis-associated speck-like protein containing caspase recruitment domain) 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.