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(s): Gonçalves, Augusto V
- Margolis, Shally R
- Quirino, Gustavo FS
- Mascarenhas, Danielle PA
- Rauch, Isabella
- Nichols, Randilea D
- Ansaldo, Eduard
- Fontana, Mary F
- Vance, Russell E
- Zamboni, Dario S
- et al.
Published Web Locationhttps://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1007886
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.
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