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PLoS One. 2019 Mar 14;14(3):e0213932. doi: 10.1371/journal.pone.0213932. eCollection 2019.

ERBB2-modulated ATG4B and autophagic cell death in human ARPE19 during oxidative stress.

Sheu SJ1,2, Chen JL1,2,3, Bee YS1,4,5, Lin SH1, Shu CW6,7.

Author information

1
Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
2
School of Medicine, National Yang-Ming University, Taipei, Taiwan.
3
Department of Optometry, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan.
4
Yuh-Ing Junior College of Health Care and Management, Kaohsiung, Taiwan.
5
National Defense Medical Center, Taipei, Taiwan.
6
School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan.
7
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.

Abstract

Age-related macular degeneration (AMD) is an ocular disease with retinal degeneration. Retinal pigment epithelium (RPE) degeneration is mainly caused by long-term oxidative stress. Kinase activity could be either protective or detrimental to cells during oxidative stress; however, few reports have described the role of kinases in oxidative stress. In this study, high-throughput screening of kinome siRNA library revealed that erb-b2 receptor tyrosine-protein kinase 2 (ERBB2) knockdown reduced reactive oxygen species (ROS) production in ARPE-19 cells during oxidative stress. Silencing ERBB2 caused an elevation in microtubule associated protein light chain C3-II (MAP1LC3B-II/I) conversion and sequesterone (SQSTM)1 protein level. ERBB2 deprivation largely caused an increase in autophagy-regulating protease (ATG4B) expression, a protease that negatively recycles MAP1LC3-II at the fusion step between the autophagosome and lysosome, suggesting ERBB2 might modulate ATG4B for autophagy induction in oxidative stress-stimulated ARPE-19 cells. ERBB2 knockdown also caused an accumulation of nuclear factor erythroid 2-related factor 2 (NRF2) and enhanced its transcriptional activity. In addition, ERBB2 ablation or treatment with autophagy inhibitors reduced oxidative-induced cytotoxic effects in ARPE-19 cells. Furthermore, ERBB2 silencing had little or no additive effects in ATG5/7-deficient cells. Taken together, our results suggest that ERBB2 may play an important role in modulating autophagic RPE cell death during oxidative stress, and ERBB2 may be a potential target in AMD prevention.

PMID:
30870514
DOI:
10.1371/journal.pone.0213932
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