Abstract
Inflammasomes are cytosolic multi-protein complexes that detect infection or cellular damage and activate the Caspase-1 (CASP1) protease. The NAIP5/NLRC4 inflammasome detects bacterial flagellin and is essential for resistance to the flagellated intracellular bacterium Legionella pneumophila. The effectors required downstream of NAIP5/NLRC4 to restrict bacterial replication remain unclear. Upon NAIP5/NLRC4 activation, CASP1 cleaves and activates the pore-forming protein Gasdermin-D (GSDMD) and the effector caspase-7 (CASP7). However, Casp1–/– (and Casp1/11–/–) mice are only partially susceptible to L. pneumophila and do not phenocopy Nlrc4–/–mice, because NAIP5/NLRC4 also activates CASP8 for restriction of L. pneumophila infection. Here we show that CASP8 promotes the activation of CASP7 and that Casp7/1/11–/– and Casp8/1/11–/– mice recapitulate the full susceptibility of Nlrc4–/– mice. Gsdmd–/– mice exhibit only mild susceptibility to L. pneumophila, but Gsdmd–/–Casp7–/– mice are as susceptible as the Nlrc4–/– mice. These results demonstrate that GSDMD and CASP7 are the key substrates downstream of NAIP5/NLRC4/CASP1/8 required for resistance to L. pneumophila.
Highlights
Inflammasomes are multi-protein complexes that assemble in the cytosol of infected or damaged cells and initiate host defense by functioning as a platform for the recruitment and activation of caspase proteases [1,2]
We further find that CASP7 activation downstream of NAIP5/ NLRC4 is mediated by CASP8 in addition to CASP1
CASP8 is activated in the absence of GSDMD and CASP1/11 for restriction of L. pneumophila replication in macrophages
Summary
Inflammasomes are multi-protein complexes that assemble in the cytosol of infected or damaged cells and initiate host defense by functioning as a platform for the recruitment and activation of caspase proteases [1,2]. The NAIP5/NLRC4 inflammasome was originally discovered as an essential host component to restrict intracellular replication of several bacterial pathogens, including Legionella pneumophila, the causative agent of a severe pneumonia called Legionnaires’ Disease [6,7]. Flagellin-deficient L. pneumophila evade detection by NAIP5/NLRC4 [11,12] and NAIP5-deficient or NLRC4-deficient cells or mice fail to detect or restrict the intracellular replication of flagellated L. pneumophila [13,14,15], but the underlying effectors downstream of NAIP5/NLRC4 required for resistance to L. pneumophila remain unclear. CASP1deficient macrophages are only partially susceptible to L. pneumophila [4,22] and the CASP8 substrates that contribute to inflammasome-mediated host defense remain unclear
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