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

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. PKR (Protein Kinase dsRNA-dependent) is one of the four eIF2α kinases which controls general protein translation and concomitantly triggers the integrative stress response through the eIF2α-independent enhanced translation of transcription factors such as ATF4 1. In addition, PKR participates in the NF-κB signaling pathways leading to induction of pro-inflammatory cytokines. For this activation, PKR may act through its kinase activity or also through protein/protein interaction 2–8. A link between PKR and the inflammasome was also reported but here, the situation is less clear as PKR has been proposed to participate in the assembly of the inflammasome, dependent 4 or not of its kinase activity 6 , to have no effect 8 or to diminish inflammasome activity through its control on translation 5. Understanding the role of PKR in the inflammation process is of particular interest in view of studies indicating its participation in neurodegenerative diseases and other human pathologies related to inflammation. For instance, following a study showing that phosphorylation of eIF-2α was impairing memory
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Stéphanie Dabo, Patrick Maillard, Milagros Collados Rodriguez, Marianne Hansen, Sabrina Mazouz, et al.. Inhibition of the inflammatory response to stress by targeting interaction between PKR and its cellular activator PACT. Scientific Reports, Nature Publishing Group, 2017, 7 (1), pp.16129. ⟨10.1038/s41598-017-16089-8⟩. ⟨pasteur-01682150⟩

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