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Research Paper|Volume 14, Issue 3|pp 1233—1252

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

Mihyang Do1, Jeongmin Park1, Yubing Chen1, So-Young Rah2, Thu-Hang Thi Nghiem1, Jeong Heon Gong1, Seong-A Ju1, Byung-Sam Kim1, Rina Yu3, Jeong Woo Park1, Stefan W. Ryter4, Young-Joon Surh5,6, Uh-Hyun Kim2, Yeonsoo Joe1, Hun Taeg Chung1
  • 1Department of Biological Sciences, University of Ulsan, Ulsan 44610, Republic of Korea
  • 2National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University Medical School, Jeonju 54907, Republic of Korea
  • 3Department of Food Science and Nutrition, University of Ulsan, Ulsan 44610, Republic of Korea
  • 4Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
  • 5Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea
  • 6Cancer Research Institute, Seoul National University, Seoul 03080, Republic of Korea
* Equal contribution
Received: August 13, 2021Accepted: February 8, 2022Published: February 15, 2022
https://doi.org/10.18632/aging.203899

Copyright: © 2022 Do et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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-1α (IRE1α) 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.