1. Gasdermin-D and Caspase-7 are the key Caspase-1/8 substrates downstream of the NAIP5/NLRC4 inflammasome required for restriction of Legionella pneumophila.
- Author
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Gonçalves AV, Margolis SR, Quirino GFS, Mascarenhas DPA, Rauch I, Nichols RD, Ansaldo E, Fontana MF, Vance RE, and Zamboni DS
- Subjects
- Animals, Apoptosis Regulatory Proteins genetics, Calcium-Binding Proteins genetics, Caspase 1 genetics, Caspase 7 genetics, Caspase 8 genetics, Inflammasomes genetics, Intracellular Signaling Peptides and Proteins, Legionnaires' Disease genetics, Legionnaires' Disease pathology, Mice, Mice, Knockout, Neuronal Apoptosis-Inhibitory Protein genetics, Phosphate-Binding Proteins, Apoptosis Regulatory Proteins immunology, Calcium-Binding Proteins immunology, Caspase 1 immunology, Caspase 7 immunology, Caspase 8 immunology, Inflammasomes immunology, Legionella pneumophila immunology, Legionnaires' Disease immunology, Neuronal Apoptosis-Inhibitory Protein immunology
- 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., Competing Interests: At the time of writing, Russell Vance was a scientific advisory board member of Metchnikoff Therapeutics, Inc. Metchnikoff Therapeutics did not fund research in his lab, or research that directly related to the research in this article. The authors have declared that no other competing interests exist.
- Published
- 2019
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