Gasdermin-D and caspase-7 are the key caspase-1/8 substrates downstream of the NAIP5/NLRC4 inflammasome required for restriction of legionella pneumophila

Augusto V. Gonçalves, Shally R. Margolis, Gustavo F.S. Quirino, Danielle P.A. Mascarenhas, Isabella Rauch, Randilea D. Nichols, Eduard Ansaldo, Mary F. Fontana, Russell E. Vance, Dario S. Zamboni

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9 Scopus citations

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.

Original languageEnglish (US)
Article numbere1007886
JournalPLoS pathogens
Volume15
Issue number6
DOIs
StatePublished - Jun 1 2019

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ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Gonçalves, A. V., Margolis, S. R., Quirino, G. F. S., Mascarenhas, D. P. A., Rauch, I., Nichols, R. D., Ansaldo, E., Fontana, M. F., Vance, R. E., & Zamboni, D. S. (2019). Gasdermin-D and caspase-7 are the key caspase-1/8 substrates downstream of the NAIP5/NLRC4 inflammasome required for restriction of legionella pneumophila. PLoS pathogens, 15(6), [e1007886]. https://doi.org/10.1371/journal.ppat.1007886