| Literature DB >> 29220654 |
Bo-Jhih Guan1, Vincent van Hoef2, Raul Jobava1, Orna Elroy-Stein3, Leos S Valasek4, Marie Cargnello5, Xing-Huang Gao1, Dawid Krokowski1, William C Merrick6, Scot R Kimball7, Anton A Komar8, Antonis E Koromilas5, Anthony Wynshaw-Boris1, Ivan Topisirovic9, Ola Larsson10, Maria Hatzoglou11.
Abstract
The integrated stress response (ISR) is a homeostatic mechanism induced by endoplasmic reticulum (ER) stress. In acute/transient ER stress, decreased global protein synthesis and increased uORF mRNA translation are followed by normalization of protein synthesis. Here, we report a dramatically different response during chronic ER stress. This chronic ISR program is characterized by persistently elevated uORF mRNA translation and concurrent gene expression reprogramming, which permits simultaneous stress sensing and proteostasis. The program includes PERK-dependent switching to an eIF3-dependent translation initiation mechanism, resulting in partial, but not complete, translational recovery, which, together with transcriptional reprogramming, selectively bolsters expression of proteins with ER functions. Coordination of transcriptional and translational reprogramming prevents ER dysfunction and inhibits "foamy cell" development, thus establishing a molecular basis for understanding human diseases associated with ER dysfunction.Entities:
Keywords: ER stress; PERK; eIF2; eIF2B; eIF3; integrated stress response; mRNA translation; protein synthesis; stress signaling; unfolded protein response
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Year: 2017 PMID： 29220654 PMCID： PMC5730339 DOI： 10.1016/j.molcel.2017.11.007
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970