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.
PACT-mediated pkr activation acts as a hyperosmotic stress intensity sensor weakening osmoadaptation and enhancing inflammation / Farabaugh, K. T.; Krokowski, D.; Guan, B. -J.; Gao, Z.; Gao, X. -H.; Wu, J.; Jobava, R.; Ray, G.; de Jesus, T. J.; Bianchi, M. G.; Chukwurah, E.; Bussolati, O.; Kilberg, M.; Buchner, D. A.; Sen, G. C.; Cotton, C.; McDonald, C.; Longworth, M.; Ramakrishnan, P.; Hatzoglou, M.. - In: ELIFE. - ISSN 2050-084X. - 9(2020). [10.7554/eLife.52241]