Phosphorylation of EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha) is indispensable for nuclear translocation of TFEB and TFE3 during ER stress

被引:23
作者
Dang, Thao Thi [1 ]
Kim, Mi-Jeong [1 ]
Lee, Yoon Young [2 ]
Le, Hien Thi [1 ]
Kim, Kook Hwan [3 ]
Nam, Somi [1 ]
Hyun, Seung Hwa [1 ]
Kim, Hong Lim [4 ]
Chung, Su Wol [1 ]
Chung, Hun Taeg [1 ]
Jho, Eek-Hoon [5 ]
Yoshida, Hiderou [6 ]
Kim, Kyoungmi [7 ]
Park, Chan Young [2 ]
Lee, Myung-Shik [8 ,9 ,10 ]
Back, Sung Hoon [1 ]
机构
[1] Univ Ulsan, Sch Biol Sci, Ulsan 44610, South Korea
[2] Ulsan Natl Inst Sci & Technol, Sch Life Sci, Dept Biol Sci, Ulsan 44919, South Korea
[3] Yonsei Univ, Coll Med, Severance Biomed Res Inst, Seoul 03722, South Korea
[4] Catholic Univ Korea, Coll Med, Integrat Res Support Ctr, Seoul, South Korea
[5] Univ Seoul, Dept Life Sci, Seoul, South Korea
[6] Univ Hyogo, Grad Sch Life Sci, Dept Mol Biochem, Hyogo 6781297, Japan
[7] Korea Univ Coll Med, Dept Biomed Sci, Dept Physiol, Seoul 02841, South Korea
[8] Soonchunhyang Univ, Dept Integrated Biomed Sci, Cheonan 31151, South Korea
[9] Soonchunhyang Univ, Soonchunhyang Inst Med bio Sci SIMS, Dept Internal Med, Div Endocrinol, Cheonan 31151, South Korea
[10] Soonchunhyang Univ, Soonchunhyang Univ Hosp, Cheonan 31151, South Korea
基金
新加坡国家研究基金会;
关键词
ATF6; autophagy; ER stress; nuclear translocation; phosphorylation TFE3; TFEB; transcription factor E3; transcription factor EB; ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; MESSENGER-RNA TRANSLATION; ALPHA-1-ANTITRYPSIN DEFICIENCY; TRANSCRIPTIONAL INDUCTION; AUTOPHAGY; PERK; EIF2-ALPHA; ADAPTATION; ATF6-ALPHA;
D O I
10.1080/15548627.2023.2173900
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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/eIF2 alpha 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/ATF6 alpha 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.
引用
收藏
页码:2111 / 2142
页数:32
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