PACT-mediated PKR activation acts as a hyperosmotic stress intensity sensor weakening osmoadaptation and enhancing inflammation

eLife

Michael Kilberg¹  Raul Jobava²  Jing Wu³  Maria Hatzoglou³  Xing-Huang Gao³  Evelyn Chukwurah³  Zhaofeng Gao³  Bo-Jhih Guan³  David A Buchner⁴  Dawid Krokowski⁵  Christine McDonald⁶  Greeshma Ray⁶  Ganes C Sen⁶  Michelle Longworth⁶  Massimiliano G Bianchi⁷  Ovidio Bussolati⁷  Parameswaran Ramakrishnan⁸  Tristan J de Jesus⁸  Kenneth T Farabaugh⁹  Calvin Cotton^1,10 

[1] Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, United States;Department of Biochemistry, Case Western Reserve University, Cleveland, United States;Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, United States;Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, United States;Department of Biochemistry, Case Western Reserve University, Cleveland, United States;Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, United States;Department of Molecular Biology, Maria Curie-Sklodowska University, Lublin, Poland;Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, United States;Department of Medicine and Surgery, Universita degli Studi di Parma, Parma, Italy;Department of Pathology, Case Western Reserve University, Cleveland, United States;Department of Pharmacology, Case Western Reserve University, Cleveland, United States;Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States;

关键词: Hyperosmotic stress;    TonEBP;    NF-κB p65;    NF-κB c-Rel;    PACT;    PKR;    Mouse;   

DOI  :  10.7554/eLife.52241

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY