PERK activation by SB202190 ameliorates amyloidogenesis via the TFEB-induced autophagy-lysosomal pathway

被引：0

作者：

Do, Mihyang ^{[1
]}

Park, Jeongmin ^{[1
]}

Chen, Yubing ^{[1
]}

Rah, So-Young ^{[2
]}

Nghiem, Thu-Hang Thi ^{[1
]}

Gong, Jeong Heon ^{[1
]}

Ju, Seong-A ^{[1
]}

Kim, Byung-Sam ^{[1
]}

Yu, Rina ^{[3
]}

Park, Jeong Woo ^{[1
]}

Ryter, Stefan W. ^{[4
]}

Surh, Young-Joon ^{[5
,6
]}

Kim, Uh-Hyun ^{[2
]}

Joe, Yeonsoo ^{[1
]}

Chung, Hun Taeg ^{[1
]}

机构：

[1] Univ Ulsan, Dept Biol Sci, Ulsan 44610, South Korea

[2] Chonbuk Natl Univ Med Sch, Natl Creat Res Lab Signaling Network Ca2, Jeonju 54907, South Korea

[3] Univ Ulsan, Dept Food Sci & Nutr, Ulsan 44610, South Korea

[4] Weill Cornell Med, Dept Med, New York, NY 10065 USA

[5] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, Seoul 08826, South Korea

[6] Seoul Natl Univ, Canc Res Inst, Seoul 03080, South Korea

来源：

AGING-US | 2022年 / 14卷 / 03期

基金：

新加坡国家研究基金会;

关键词：

amyloidogenesis; mitochondrial reactive oxygen species; PERK; transcription factor-EB; autophagy-lysosome pathway; ENDOPLASMIC-RETICULUM STRESS; MOUSE MODEL; NEURODEGENERATION; CALCINEURIN; PROTEINS; PROTECTS; GENES;

D O I：

暂无

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK), a key ER stress sensor of the unfolded protein response (UPR), can confer beneficial effects by facilitating the removal of cytosolic aggregates through the autophagy-lysosome pathway (ALP). In neurodegenerative diseases, the ALP ameliorates the accumulation of intracellular protein aggregates in the brain. Transcription factor-EB (TFEB), a master regulator of the ALP, positively regulates key genes involved in the cellular degradative pathway. However, in neurons, the role of PERK activation in mitigating amyloidogenesis by ALP remains unclear. In this study, we found that SB202190 selectively activates PERK independently of its inhibition of p38 mitogen-activated protein kinase, but not inositol-requiring transmembrane kinase/endoribonuclease-1 alpha (IRE1 alpha) or activating transcription factor 6 (ATF6), in human neuroblastoma cells. PERK activation by SB202190 was dependent on mitochondrial ROS production and promoted Ca2+-calcineurin activation. The activation of the PERK-Ca2+-calcineurin axis by SB202190 positively affects TFEB activity to increase ALP in neuroblastoma cells. Collectively, our study reveals a novel physiological mechanism underlying ALP activation, dependent on PERK activation, for ameliorating amyloidogenesis in neurodegenerative diseases.

引用

页码：1233 / 1252

页数：20

共 43 条

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