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The Rel family of transcription factors TonEBP and NF-\u03baB 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-\u03baB c-Rel and TonEBP essential for the increased expression of TonEBP-dependent osmoprotective genes. This resulted in enhanced formation of TonEBP\/NF-\u03baB 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.<\/jats:p>","DOI":"10.7554\/elife.52241","type":"journal-article","created":{"date-parts":[[2020,3,16]],"date-time":"2020-03-16T09:00:19Z","timestamp":1584349219000},"source":"Crossref","is-referenced-by-count":32,"title":["PACT-mediated PKR activation acts as a hyperosmotic stress intensity sensor weakening osmoadaptation and enhancing inflammation"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9591-0466","authenticated-orcid":true,"given":"Kenneth T","family":"Farabaugh","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Case Western Reserve University, Cleveland, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawid","family":"Krokowski","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genome Sciences, Case Western Reserve University, 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