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

Publication date: 25 July 2017
Source:Cell Reports, Volume 20, Issue 4
Author(s): 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
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.

Graphical abstract

Teaser

Cunha et al. find that the AIM2 inflammasome is activated in response to Legionella and cooperates with caspase-11 to trigger host resistance. Mechanistically, AIM2 engages active but unprocessed caspase-1 to trigger pore formation and K⁺ efflux, which also converges into NLRP3 activation. Thus, the AIM2 inflammasome cooperates with caspase-11 to amplify the signals of infection and triggers noncanonical activation of the NLRP3 inflammasome.


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