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)

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: Ritchie, Dr Neil and Bayes, Dr Hannah and Evans, Professor Tom
• 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 > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
55868	1	The Proinflammatory Th17 Response as a Therapeutic Target in Cystic Fibrosis Lung Disease	Tom Evans	Wellcome Trust (WELLCOME)	094779/Z/10/Z	III - BACTERIOLOGY
55868	2	The Proinflammatory Th17 Response as a Therapeutic Target in Cystic Fibrosis Lung Disease	Tom Evans	Wellcome Trust (WELLCOME)	094779/Z/12A	III - BACTERIOLOGY