The regulation of the ZBP1‐NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis)

Abstract ZBP1 has been characterized as a critical innate immune sensor of not only viral RNA products but also endogenous nucleic acid ligands. ZBP1 sensing of the Z‐RNA produced during influenza virus infection induces cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). PANoptosis is a coordinated cell death pathway that is driven through a multiprotein complex called the PANoptosome and enables crosstalk and co‐regulation among these processes. During influenza virus infection, a key step in PANoptosis and PANoptosome assembly is the formation of the ZBP1‐NLRP3 inflammasome. When Z‐RNA is sensed, ZBP1 recruits RIPK3 and caspase‐8 to activate the ZBP1‐NLRP3 inflammasome. Several other host factors have been found to be important for ZBP1‐NLRP3 inflammasome assembly, including molecules involved in the type I interferon signaling pathway and caspase‐6. Additionally, influenza viral proteins, such as M2, NS1, and PB1‐F2, have also been shown to regulate the ZBP1‐NLRP3 inflammasome. This review explains the functions of ZBP1 and the mechanistic details underlying the activation of the ZBP1‐NLRP3 inflammasome and the formation of the PANoptosome. Improved understanding of the ZBP1‐NLRP3 inflammasome will direct the development of therapeutic strategies to target infectious and inflammatory diseases.