RESUMO

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.

Assuntos

Proteínas Reguladoras de Apoptose/imunologia , Proteínas de Ligação ao Cálcio/imunologia , Caspase 1/imunologia , Caspase 7/imunologia , Caspase 8/imunologia , Inflamassomos/imunologia , Legionella pneumophila/imunologia , Doença dos Legionários/imunologia , Proteína Inibidora de Apoptose Neuronal/imunologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas de Ligação ao Cálcio/genética , Caspase 1/genética , Caspase 7/genética , Caspase 8/genética , Inflamassomos/genética , Peptídeos e Proteínas de Sinalização Intracelular , Doença dos Legionários/genética , Doença dos Legionários/patologia , Camundongos , Camundongos Knockout , Proteína Inibidora de Apoptose Neuronal/genética , Proteínas de Ligação a Fosfato