IRE1α mediates PKR activation in response to Chlamydia trachomatis infection.

Autor: Webster SJ; Rheumatology Research Group, Department of Medicine, University of Cambridge, UK., Ellis L; Rheumatology Research Group, Department of Medicine, University of Cambridge, UK., O'Brien LM; Rheumatology Research Group, Department of Medicine, University of Cambridge, UK., Tyrrell B; Rheumatology Research Group, Department of Medicine, University of Cambridge, UK., Fitzmaurice TJ; Rheumatology Research Group, Department of Medicine, University of Cambridge, UK., Elder MJ; Rheumatology Research Group, Department of Medicine, University of Cambridge, UK., Clare S; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK., Chee R; Department of Immunology, Royal Free Hospital, London, UK., Gaston JS; Rheumatology Research Group, Department of Medicine, University of Cambridge, UK., Goodall JC; Rheumatology Research Group, Department of Medicine, University of Cambridge, UK. Electronic address: jcg23@medschl.cam.ac.uk.
Jazyk: angličtina
Zdroj: Microbes and infection [Microbes Infect] 2016 Jul-Aug; Vol. 18 (7-8), pp. 472-83. Date of Electronic Publication: 2016 Mar 26.
DOI: 10.1016/j.micinf.2016.03.010
Abstrakt: Protein kinase RNA activated (PKR) is a crucial mediator of anti-viral responses but is reported to be activated by multiple non-viral stimuli. However, mechanisms underlying PKR activation, particularly in response to bacterial infection, remain poorly understood. We have investigated mechanisms of PKR activation in human primary monocyte-derived dendritic cells in response to infection by Chlamydia trachomatis. Infection resulted in potent activation of PKR that was dependent on TLR4 and MyD88 signalling. NADPH oxidase was dispensable for activation of PKR as cells from chronic granulomatous disease (CGD) patients, or mice that lack NADPH oxidase activity, had equivalent or elevated PKR activation. Significantly, stimulation of cells with endoplasmic reticulum (ER) stress-inducing agents resulted in potent activation of PKR that was blocked by an inhibitor of IRE1α RNAse activity. Crucially, infection resulted in robust IRE1α RNAse activity that was dependent on TLR4 signalling and inhibition of IRE1α RNAse activity prevented PKR activation. Finally, we demonstrate that TLR4/IRE1α mediated PKR activation is required for the enhancement of interferon-β production following C. trachomatis infection. Thus, we provide evidence of a novel mechanism of PKR activation requiring ER stress signalling that occurs as a consequence of TLR4 stimulation during bacterial infection and contributes to inflammatory responses.
(Copyright © 2016 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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