RIPK1 Distinctly Regulates <i>Yersinia</i>-Induced Inflammatory Cell Death, PANoptosis

Abstract

Bacterial pathogens from the genus <i>Yersinia</i> cause fatal sepsis and gastritis in humans. Innate immune signaling and inflammatory cell death (pyroptosis, apoptosis, and necroptosis [PANoptosis]) serve as a first line of antimicrobial host defense. The receptor-interacting protein kinase 1 (RIPK1) is essential for <i>Yersinia</i>-induced pyroptosis and apoptosis and an effective host response. However, it is not clear whether RIPK1 assembles a multifaceted cell death complex capable of regulating caspase-dependent pyroptosis and apoptosis or whether there is cross-talk with necroptosis under these conditions. In this study, we report that <i>Yersinia</i> activates PANoptosis, as evidenced by the concerted activation of proteins involved in PANoptosis. Genetic deletion of RIPK1 abrogated the <i>Yersinia</i>-induced activation of the inflammasome/pyroptosis and apoptosis but enhanced necroptosis. We also found that <i>Yersinia</i> induced assembly of a RIPK1 PANoptosome complex capable of regulating all three branches of PANoptosis. Overall, our results demonstrate a role for the RIPK1 PANoptosome in <i>Yersinia</i>-induced inflammatory cell death and host defense.