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Bacterial infection can trigger autophagy and inflammasome activation, but the effects of inflammasome activation on autophagy are unknown. We examined this in the context of Pseudomonas aeruginosa macrophage infection, which triggers NLRC4 inflammasome activation. P. aeruginosa induced autophagy via TLR4 and its adaptor TRIF. NLRC4 and caspase-1 activation following infection attenuated autophagy. Caspase-1 directly cleaved TRIF to diminish TRIF-mediated signaling, resulting in inhibition of autophagy and in reduced type I interferon production. Expression of a caspase-1 resistant TRIF mutant enhanced autophagy and type I interferon production following infection. Preventing TRIF cleavage by caspase-1 in an in vivo model of P. aeruginosa infection resulted in enhanced bacterial autophagy, attenuated IL-1β production, and increased bacterial clearance. Additionally, TRIF cleavage by caspase-1 diminished NLRP3 inflammasome activation. Thus, caspase-1 mediated TRIF cleavage is a key event in controlling autophagy, type I interferon production, and inflammasome activation with important functional consequences.

Original publication

DOI

10.1016/j.chom.2014.01.010

Type

Journal article

Journal

Cell host microbe

Publication Date

12/02/2014

Volume

15

Pages

214 - 227

Keywords

Adaptor Proteins, Vesicular Transport, Animals, Apoptosis Regulatory Proteins, Autophagy, Calcium-Binding Proteins, Caspase 1, Cells, Cultured, Hydrolysis, Interferon-beta, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Pseudomonas aeruginosa, Toll-Like Receptor 4