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IRE1α mediates PKR activation in response to Chlamydia trachomatis infection.

Published version
Peer-reviewed

Change log

Authors

Webster, Steve J 
Ellis, Lou 
O'Brien, Louise M 
Tyrrell, Beatrice 
Fitzmaurice, Timothy J 

Abstract

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.

Description

Keywords

Chlamydia, ER stress, PKR, Cells, Cultured, Chlamydia trachomatis, Endoribonucleases, Host-Pathogen Interactions, Humans, Monocytes, Myeloid Differentiation Factor 88, Protein Serine-Threonine Kinases, Signal Transduction, Toll-Like Receptor 4, eIF-2 Kinase

Journal Title

Microbes Infect

Conference Name

Journal ISSN

1286-4579
1769-714X

Volume Title

18

Publisher

Elsevier BV
Sponsorship
Medical Research Council (G1001765)
Arthritis Research Uk (None)
Arthritis Research Uk (None)