PACT-mediated PKR activation acts as a hyperosmotic stress intensity sensor weakening osmoadaptation and enhancing inflammation
- Case Western Reserve University, United States
- Cleveland Clinic Foundation, United States
- Universita degli Studi di Parma, Italy
- University of Parma, Italy
- University of Florida, United States
Abstract
The inability of cells to adapt to increased environmental tonicity can lead to inflammatory gene expression and pathogenesis. The Rel family of transcription factors TonEBP and NF-κB p65 play critical roles in the switch from osmoadaptive homeostasis to inflammation, respectively. Here we identified PACT-mediated PKR kinase activation as a marker of the termination of adaptation and initiation of inflammation in Mus musculus embryonic fibroblasts. We found that high stress-induced PACT-PKR activation inhibits the interaction between NF-κB c-Rel and TonEBP essential for the increased expression of TonEBP-dependent osmoprotective genes. This resulted in enhanced formation of TonEBP/NF-κB p65 complexes and enhanced proinflammatory gene expression. These data demonstrate a novel role of c-Rel in the adaptive response to hyperosmotic stress, which is inhibited via a PACT/PKR-dependent dimer redistribution of the Rel family transcription factors. Our results suggest that inhibiting PACT-PKR signaling may prove a novel target for alleviating stress-induced inflammatory diseases.
Data availability
Sequencing data have been deposited in GEO under accession code GSE138692.
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RNA-sequencing in Mouse Embryonic Fibroblasts exposed to different Intensities of Hyperosmotic StressNCBI Gene Expression Omnibus, GSE138692.
Article and author information
Author details
Kenneth T Farabaugh
Parameswaran Ramakrishnan
Funding
National Institutes of Health (R01DK53307; R01DK060596; R01DK113196)
- Maria Hatzoglou
National Institute of Allergy and Infectious Diseases (R01AI116730; R21AI144264)
- Parameswaran Ramakrishnan
National Science Centre (2018/30/E/NZ1/00605)
- Dawid Krokowski
Cleveland Digestive Disease Research Core Center (DK097948)
- Maria Hatzoglou
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Mary X O'Riordan, University of Michigan Medical School, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#400061) of Case Western Reserve University.
Version history
- Received: September 27, 2019
- Accepted: March 14, 2020
- Accepted Manuscript published: March 16, 2020 (version 1)
- Version of Record published: April 9, 2020 (version 2)
Copyright
© 2020, Farabaugh et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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PACT-mediated PKR activation acts as a hyperosmotic stress intensity sensor weakening osmoadaptation and enhancing inflammation
eLife 9:e52241.
https://doi.org/10.7554/eLife.52241
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