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.
Highlights
Caspase-11 is a key mediator of the murine innate immune response to cytosolic Gram-negative bacterial pathogens, by allowing the recognition of bacterial LPS (Hagar et al, 2013; Kayagaki et al, 2013; Shi et al, 2014)
Cytosolic LPS engages the non-canonical pathway of inflammasome activation, whereby active caspase-11 cleaves its substrate gasdermin D (GSDMD) to generate a GSDMDp30 fragment that forms pores in the plasma membrane (He et al, 2015; Kayagaki et al, 2015; Shi et al, 2015; Aglietti et al, 2016; Ding et al, 2016; Liu et al, 2016)
Caspase-11 cleavage to p32 was not a consequence of NLRP3 signalling; p32 generation was not blocked by MCC950, nor was it suppressed in Casp-1C284A bone marrow macrophages (BMMs) in which the catalytic cysteine of this protease is mutated to disable caspase-1 activity (Fig 1D and E)
Summary
Caspase-11 is a key mediator of the murine innate immune response to cytosolic Gram-negative bacterial pathogens, by allowing the recognition of bacterial LPS (Hagar et al, 2013; Kayagaki et al, 2013; Shi et al, 2014). Cytosolic LPS engages the non-canonical pathway of inflammasome activation, whereby active caspase-11 cleaves its substrate gasdermin D (GSDMD) to generate a GSDMDp30 fragment that forms pores in the plasma membrane (He et al, 2015; Kayagaki et al, 2015; Shi et al, 2015; Aglietti et al, 2016; Ding et al, 2016; Liu et al, 2016). LPS is proposed to be a direct ligand for caspase-11, wherein LPS interaction with the caspase-11 CARD domain facilitates activation of the protease domain (Shi et al, 2014), via an undetermined mechanism
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