2010
Differential Requirement for Caspase-1 Autoproteolysis in Pathogen-Induced Cell Death and Cytokine Processing
Abstract: Summary Activation of the cysteine protease Caspase-1 is a key event in the innate immune response to infections. Synthesized as a pro-protein, Caspase-1 undergoes autoproteolysis within multi-protein complexes called inflammasomes. Activated Caspase-1 is required for proteolytic processing and release of the cytokines interleukin-1β and interleukin-18, and can also cause rapid macrophage cell death. We show that macrophage cell death and cytokine maturation in response to infection with diverse bacterial path…
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Cited by 599 publications
(686 citation statements)
References 38 publications
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“…Indeed, there is robust processing and secretion of caspase-11 in response to WT and Δ flaA Lp (Figure S2). In accordance with previous findings [26], [53], caspase-1 is absolutely required for IL-1β secretion. In contrast, we observe robust IL-1α release even in the absence of caspase-1.…”
Section: Resultssupporting
confidence: 93%
“…Indeed, there is robust processing and secretion of caspase-11 in response to WT and Δ flaA Lp (Figure S2). In accordance with previous findings [26], [53], caspase-1 is absolutely required for IL-1β secretion. In contrast, we observe robust IL-1α release even in the absence of caspase-1.…”
Section: Resultssupporting
confidence: 93%
“…To test if the catalytic activity of caspase-1 is required for IL-1α secretion in response to L. pneumophila , we inhibited caspase-1 catalytic activity with the pharmacological inhibitor YVAD-cmk (YVAD). Consistent with previous studies [53], IL-1β secretion in response to L. pneumophila is substantially inhibited by YVAD. However, YVAD has no effect on IL-1α secretion, indicating that IL-1α release in response to L. pneumophila does not require caspase-1 catalytic activity (Figure 1C), as has been shown for other inflammasome activators [55].…”
Section: Resultssupporting
confidence: 92%
“…3 E ). In agreement with previous research ( Broz et al, 2010 ), pyroptosis, and thus GSDMD N-terminal fragment, was not observed in casp-1/11 −/− cells but was cleaved in Asc −/− cells comparably with WT cells ( Fig. 3 E ).…”
Section: Resultssupporting
confidence: 93%
“…We have generated and analyzed mice expressing enzymatically inactive caspase-1 C284A , which we have named Casp1 mlt . In contrast to the previous observation that biochemical inhibition of caspase-1 by peptide-based inhibitors selectively blocks IL-1β cleavage but does not prevent pyroptosis or IL-1 secretion ( Broz et al., 2010 , Cullen et al., 2015 , Groß et al., 2012 ), genetic inactivation of caspase-1 protease activity prevented not only IL-1β cleavage but also canonical IL-1 secretion and pyroptosis at early time points after inflammasome activation. The inability of Ac-YVAD-cmk to block cleavage of the pyroptotic effector GSDMD explains this discrepancy.…”
Section: Discussioncontrasting
confidence: 98%
