A Unique ISR Program Determines Cellular Responses to Chronic Stress

0483711 - MBÚ 2018 RIV US eng J - Journal Article
Guan, B.J. - van Hoef, V. - Jobava, R. - Elroy-Stein, O. - Valášek, Leoš Shivaya - Cargnello, M. - Gao, X.H. - Krokowski, D. - Merrick, W.C. - Kimball, S.R. - Komar, A.A. - Koromilas, A.E. - Wynshaw-Boris, A. - Topisirovic, I. - Larsson, O. - Hatzoglou, M.
A Unique ISR Program Determines Cellular Responses to Chronic Stress.
Molecular Cell. Roč. 68, č. 5 (2017), s. 885-900. ISSN 1097-2765. E-ISSN 1097-4164
R&D Projects: GA ČR(CZ) GA17-06238S
EU Projects: Wellcome Trust(GB) 090812/B/09/A
Institutional support: RVO:61388971
Keywords : UNFOLDED PROTEIN RESPONSE * EUKARYOTIC TRANSLATION INITIATION * ENDOPLASMIC-RETICULUM STRESS
OECD category: Microbiology
Impact factor: 14.248, year: 2017

The integrated stress response (ISR) is a homeostatic mechanisminduced 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.
Permanent Link: http://hdl.handle.net/11104/0278913