Phosphorylation of EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha) is indispensable for nuclear translocation of TFEB and TFE3 during ER stress
Authors and Affiliations
Authors and Affiliations
Thao Thi Dang 1, Mi-Jeong Kim 1, Yoon Young Lee 2, Hien Thi Le 1, Kook Hwan Kim 3, Somi Nam 1, Seung Hwa Hyun 1, Hong Lim Kim 4, Su Wol Chung 1, Hun Taeg Chung 1, Eek-Hoon Jho 5, Hiderou Yoshida 6, Kyoungmi Kim 7, Chan Young Park 2, Myung-Shik Lee 8, Sung Hoon Back 1
1School of Biological Sciences, University of Ulsan, Ulsan, 44610, Korea.
2Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, 44919, Korea.
3Severance Biomedical Research Institute, Yonsei University College of Medicine, 03722, Seoul, Korea.
4Integrative Research Support Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
5Department of Life Science, University of Seoul, Seoul, Korea.
6Department of Molecular Biochemistry, Graduate School of Life Science, University of Hyogo, 678-1297, Hyogo, Japan.
7Department of Biomedical Sciences and Department of Physiology, Korea University College of Medicine, 02841, Seoul, Korea.
8Department of Integrated Biomedical Science & Division of Endocrinology, Department of Internal Medicine, SIMS (Soonchunhyang Institute of Medi-bio Science) & Soonchunhyang University Hospital, Soonchunhyang University, 31151, Cheonan, Korea.
Correspondence : Sung Hoon Back
There are diverse links between macroautophagy/autophagy pathways and unfolded protein response (UPR) pathways under endoplasmic reticulum (ER) stress conditions to restore ER homeostasis. Phosphorylation of EIF2S1/eIF2α is an important mechanism that can regulate all three UPR pathways through transcriptional and translational reprogramming to maintain cellular homeostasis and overcome cellular stresses. In this study, to investigate the roles of EIF2S1 phosphorylation in regulation of autophagy during ER stress, we used EIF2S1 phosphorylation-deficient (A/A) cells in which residue 51 was mutated from serine to alanine. A/A cells exhibited defects in several steps of autophagic processes (such as autophagosome and autolysosome formation) that are regulated by the transcriptional activities of the autophagy master transcription factors TFEB and TFE3 under ER stress conditions. EIF2S1 phosphorylation was required for nuclear translocation of TFEB and TFE3 during ER stress. In addition, EIF2AK3/PERK, PPP3/calcineurin-mediated dephosphorylation of TFEB and TFE3, and YWHA/14-3-3 dissociation were required for their nuclear translocation, but were insufficient to induce their nuclear retention during ER stress. Overexpression of the activated ATF6/ATF6α form, XBP1s, and ATF4 differentially rescued defects of TFEB and TFE3 nuclear translocation in A/A cells during ER stress. Consequently, overexpression of the activated ATF6 or TFEB form more efficiently rescued autophagic defects, although XBP1s and ATF4 also displayed an ability to restore autophagy in A/A cells during ER stress. Our results suggest that EIF2S1 phosphorylation is important for autophagy and UPR pathways, to restore ER homeostasis and reveal how EIF2S1 phosphorylation connects UPR pathways to autophagy.