AIM2 Engages Active but Unprocessed Caspase-1 to Induce Noncanonical Activation of the NLRP3 Inflammasome

Larissa D. Cunha; Alexandre L.N. Silva; Juliana M. Ribeiro; Danielle P.A. Mascarenhas; Gustavo F.S. Quirino; Leonardo L. Santos; Richard A. Flavell; Dario S. Zamboni

AIM2 Engages Active but Unprocessed Caspase-1 to Induce Noncanonical Activation of the NLRP3 Inflammasome

2017

Inflammasomes are multimeric protein complexes that initiate inflammatory cascades. Their activation is a hallmark of many infectious or inflammatory diseases. Their composition and activity are specified by proinflammatory stimuli. For example, the NLRP3 inflammasome is activated in response to cell damage and K+ efflux, whereas the AIM2 inflammasome is activated in response to cytosolic DNA. We used Legionella pneumophila, an intracellular bacterial pathogen that activates multiple inflammasomes, to elucidate the molecular mechanisms regulating inflammasome activation during infection. Upon infection, the AIM2 inflammasome engaged caspase-1 to induce pore formation in the cell membrane, which then caused K+-efflux-mediated activation of NLRP3. Thus, the AIM2 inflammasome amplifies signals of infection, triggering noncanonical activation of NLRP3. During infection, AIM2 and caspase-11 induced membrane damage, which was sufficient and essential for activating the NLRP3 inflammasome. Our data reveal that different inflammasomes regulate one another’s activity to ensure an effective immune response to infection.

Показать больше [+]