Caspase-1 cleavage of the TLR adaptor TRIF inhibits autophagy and β-interferon production during pseudomonas aeruginosa infection

Jabir, M. S. et al. (2014) Caspase-1 cleavage of the TLR adaptor TRIF inhibits autophagy and β-interferon production during pseudomonas aeruginosa infection. Cell Host and Microbe, 15(2), pp. 214-227. (doi:10.1016/j.chom.2014.01.010) (PMID:24528867)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Evans, Professor Tom and Ritchie, Dr Neil and Bayes, Dr Hannah
Authors: Jabir, M. S., Ritchie, N. D., Li, D., Bayes, H. K., Tourlomousis, P., Puleston, D., Lupton, A., Hopkins, L., Simon, A. K., Bryant, C., and Evans, T. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cell Host and Microbe
Publisher:Elsevier Inc.
ISSN:1931-3128
ISSN (Online):1934-6069
Copyright Holders:Copyright © 2014 Elsevier Inc.
First Published:First published in Cell Host and Microbe 15(2):214-227
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
558681The Proinflammatory Th17 Response as a Therapeutic Target in Cystic Fibrosis Lung DiseaseTom EvansWellcome Trust (WELLCOME)094779/Z/10/ZIII - BACTERIOLOGY
558682The Proinflammatory Th17 Response as a Therapeutic Target in Cystic Fibrosis Lung DiseaseTom EvansWellcome Trust (WELLCOME)094779/Z/12AIII - BACTERIOLOGY