Inhibition of the inflammatory response to stress by targeting interaction between PKR and its cellular activator PACT

Dabo, S. et al. (2017) Inhibition of the inflammatory response to stress by targeting interaction between PKR and its cellular activator PACT. Scientific Reports, 7, 16129. (doi: 10.1038/s41598-017-16089-8) (PMID:29170442) (PMCID:PMC5701060)

Abstract

PKR is a cellular kinase involved in the regulation of the integrative stress response (ISR) and pro-inflammatory pathways. Two N-terminal dsRNA Binding Domains (DRBD) are required for activation of PKR, by interaction with either dsRNA or PACT, another cellular DRBD-containing protein. A role for PKR and PACT in inflammatory processes linked to neurodegenerative diseases has been proposed and raised interest for pharmacological PKR inhibitors. However, the role of PKR in inflammation is subject to controversy. We identified the flavonoid luteolin as an inhibitor of the PKR/PACT interaction at the level of their DRBDs using high-throughput screening of chemical libraries by homogeneous time-resolved fluorescence. This was further validated using NanoLuc-Based Protein Complementation Assay. Luteolin inhibits PKR phosphorylation, the ISR and the induction of pro-inflammatory cytokines in human THP1 macrophages submitted to oxidative stress and toll-like receptor (TLR) agonist. Similarly, luteolin inhibits induction of pro-inflammatory cytokines in murine microglial macrophages. In contrast, luteolin increased activation of the inflammasome, in a PKR-independent manner. Collectively, these data delineate the importance of PKR in the inflammation process to the ISR and induction of pro-inflammatory cytokines. Pharmacological inhibitors of PKR should be used in combination with drugs targeting directly the inflammasome.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Collados Rodriguez, Dr Milagros
• Authors: Dabo, S., Maillard, P., Collados Rodriguez, M., Hansen, M. D., Mazouz, S., Bigot, D.-J., Tible, M., Janvier, G., Helynck, O., Cassonnet, P., Jacob, Y., Bellaou, J., Gatignol, A., Patel, R. C., Hugon, J., Munier-Lehmann, H., and Meurs, E. F.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Scientific Reports
• Publisher: Nature Publishing Group
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Scientific Reports 7: 16129
• Publisher Policy: Reproduced under a Creative Commons License