Caspase-11 auto-proteolysis is crucial for noncanonical inflammasome activation.

ABSTRACT: Intracellular LPS sensing by caspase-4/5/11 triggers proteolytic activation of pore-forming gasdermin D (GSDMD), leading to pyroptotic cell death in Gram-negative bacteria-infected cells. Involvement of caspase-4/5/11 and GSDMD in inflammatory responses, such as lethal sepsis, makes them highly desirable drug targets. Using knock-in (KI) mouse strains, we herein provide genetic evidence to show that caspase-11 auto-cleavage at the inter-subunit linker is essential for optimal catalytic activity and subsequent proteolytic cleavage of GSDMD. Macrophages from caspase-11-processing dead KI mice (Casp11^{Prc D285A/D285A} ) exhibit defective caspase-11 auto-processing and phenocopy Casp11^-/- and caspase-11 enzymatically dead KI (Casp11^{Enz C254A/C254A}

SUBMITTER: Lee BL 

PROVIDER: S-EPMC6122968 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature