Journal
MICROBES AND INFECTION
Volume 18, Issue 7-8, Pages -Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.micinf.2016.03.010
Keywords
PKR; ER stress; Chlamydia
Categories
Funding
- MRC grant [RG61445]
- Arthritis Research Senior Fellowship [RG61798]
- NIHR Cambridge Biomedical Research Centre
- Cambridge Arthritis Research Endeavour (CARE)
- MRC [G1001765] Funding Source: UKRI
- Medical Research Council [G1001765] Funding Source: researchfish
- Versus Arthritis [19962, 19639] Funding Source: researchfish
Ask authors/readers for more resources
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 IRE1 alpha RNAse activity. Crucially, infection resulted in robust IRE1 alpha RNAse activity that was dependent on TLR4 signalling and inhibition of IRE1 alpha RNAse activity prevented PKR activation. Finally, we demonstrate that TLR4/IRE1 alpha mediated PKR activation is required for the enhancement of interferon-beta 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. (C) 2016 The Authors. Published by Elsevier Masson SAS on behalf of Institut Pasteur.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available