Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense

Caspases regulate cell death, immune responses, and homeostasis. Caspase-6 is categorized as an executioner Caspase but shows key differences from the other executioners. Overall, little is known about the functions of caspase-6 in biological processes apart from Apoptosis. Here, we show that caspase-6 mediates innate immunity and inflammasome activation. Furthermore, we demonstrate that caspase-6 promotes the activation of programmed cell death pathways including Pyroptosis, Apoptosis, and Necroptosis (PANoptosis) and plays an essential role in host defense against influenza A virus (IAV) Infection. In addition, caspase-6 promoted the differentiation of alternatively activated macrophages (AAMs). Caspase-6 facilitated the RIP homotypic interaction motif (RHIM)-dependent binding of RIPK3 to ZBP1 via its interaction with RIPK3. Altogether, our findings reveal a vital role for caspase-6 in facilitating ZBP1-mediated inflammasome activation, cell death, and host defense during IAV Infection, opening additional avenues for treatment of infectious and autoinflammatory diseases and Cancer.

AAMs; NLRP3; PANoptosis; RIPK1; RIPK3; ZBP1; apoptosis; caspase-1; caspase-6; caspase-8; inflammasome; influenza A virus; necroptosis; pyroptosis.