Newly Identified Function of Caspase-6 in ZBP1-mediated Innate Immune Responses, NLRP3 Inflammasome Activation, PANoptosis, and Host Defense.

Caspase-6 was discovered decades ago, but its roles in biological processes remain largely unknown. Recently, we have demonstrated that caspase-6 plays a critical role in influenza A virus (IAV)-induced cell death and innate immune responses. During IAV infection, Z-DNA binding protein 1 (ZBP1) initiates ZBP1-PANoptosome assembly to drive inflammasome activation and cell death, and we showed that caspase-6 interacts with RIPK3 to enhance the interaction between RIPK3 and ZBP1, thus promoting PANoptosome assembly. Moreover, the caspase activity of caspase-6 is not required for tins process, suggesting a caspase-independent function of caspase-6 during IAV infection. Additionally, we found that caspase-6 is required for the alternative activation of alveolar macrophages in response to IAV infection. Our findings provide an opportunity to reconsider the physiological role of caspase-6.