ERBB2-modulated ATG4B and autophagic cell death in human ARPE19 during oxidative stress.
Shwu-Jiuan SheuJiunn-Liang ChenYoun-Shen BeeShi-Han LinChih-Wen ShuPublished in: PloS one (2019)
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.
Keyphrases
- oxidative stress
- induced apoptosis
- cell death
- cell cycle arrest
- endoplasmic reticulum stress
- tyrosine kinase
- diabetic rats
- signaling pathway
- dna damage
- ischemia reperfusion injury
- age related macular degeneration
- gene expression
- reactive oxygen species
- poor prognosis
- emergency department
- protein kinase
- drug delivery
- endothelial cells
- drug induced
- simultaneous determination
- immune response
- binding protein
- fluorescent probe
- induced pluripotent stem cells
- climate change