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Life Sci Alliance. 2018 Dec 6;1(6):e201800237. doi: 10.26508/lsa.201800237. eCollection 2018 Dec.

Dimerization and auto-processing induce caspase-11 protease activation within the non-canonical inflammasome.

Author information

1
Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, The University of Queensland, St Lucia, Australia.

Abstract

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.

Conflict of interest statement

K Schroder is a co-inventor on patent applications for NLRP3 inhibitors which have been licensed to Inflazome Ltd, a company headquartered in Dublin, Ireland. Inflazome is developing drugs that target the NLRP3 inflammasome to address unmet clinical needs in inflammatory disease. K Schroder served on the Scientific Advisory Board of Inflazome in 2016–2017. The authors have no further conflicts of interest to declare.

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