TY - JOUR T1 - Dimerization and auto-processing induce caspase-11 protease activation within the non-canonical inflammasome JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201800237 VL - 1 IS - 6 SP - e201800237 AU - Connie Ross AU - Amy H Chan AU - Jessica Von Pein AU - Dave Boucher AU - Kate Schroder Y1 - 2018/12/01 UR - https://www.life-science-alliance.org/content/1/6/e201800237.abstract N2 - Caspase-11 is a cytosolic sensor and protease that drives innate immune responses to the bacterial cell wall component, LPS. Caspase-11 provides defence against cytosolic Gram-negative bacteria; however, excessive caspase-11 responses contribute to murine endotoxic shock. Upon sensing LPS, caspase-11 assembles a higher order structure called the non-canonical inflammasome that enables the activation of caspase-11 protease function, leading to gasdermin D cleavage and cell death. The mechanism by which caspase-11 acquires protease function is, however, poorly defined. Here, we show that caspase-11 dimerization is necessary and sufficient for eliciting basal caspase-11 protease function, such as the ability to auto-cleave. We further show that during non-canonical inflammasome signalling, caspase-11 self-cleaves at site (D285) within the linker connecting the large and small enzymatic subunits. Self-cleavage at the D285 site is required to generate the fully active caspase-11 protease (proposed here to be p32/p10) that mediates gasdermin D cleavage, macrophage death, and NLRP3-dependent IL-1β production. This study provides a detailed molecular mechanism by which LPS induces caspase-11–driven inflammation and cell death to provide host defence against cytosolic bacterial infection. ER -