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.

• Klíčová slova
• ER stress, PERK, eIF2, eIF2B, eIF3, integrated stress response, mRNA translation, protein synthesis, stress signaling, unfolded protein response,
• MeSH
• časové faktory MeSH
• eukaryotický iniciační faktor 3 genetika   metabolismus   MeSH
• fenotyp MeSH
• fibroblasty metabolismus   patologie   MeSH
• genetická transkripce * MeSH
• HEK293 buňky MeSH
• homeostáze proteinů MeSH
• kinasa eIF-2 genetika   metabolismus   MeSH
• lidé MeSH
• messenger RNA biosyntéza   genetika   MeSH
• myši MeSH
• otevřené čtecí rámce MeSH
• přeprogramování buněk MeSH
• proteosyntéza * MeSH
• RNA interference MeSH
• signální transdukce MeSH
• stres endoplazmatického retikula * MeSH
• transfekce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• eukaryotický iniciační faktor 3 MeSH
• kinasa eIF-2 MeSH
• messenger RNA MeSH
• PERK kinase MeSH Prohlížeč