https://scholars.lib.ntu.edu.tw/handle/123456789/595887
標題: | K48/K63-linked polyubiquitination of ATG9A by TRAF6 E3 ligase regulates oxidative stress-induced autophagy | 作者: | Wang, Yi Ting Liu, Ting Yu Shen, Chia Hsing Lin, Shu Yu Hung, Chin Chun LI-CHUNG HSU Chen, Guang Chao |
關鍵字: | ATG9A | autophagy | oxidative stress | TRAF6 | VPS34 complex | 公開日期: | 22-二月-2022 | 卷: | 38 | 期: | 8 | 來源出版物: | Cell Reports | 摘要: | Excessive generation and accumulation of highly reactive oxidizing molecules causes oxidative stress and oxidative damage to cellular components. Accumulating evidence indicates that autophagy diminishes oxidative damage in cells and maintains redox homeostasis by degrading and recycling intracellular damaged components. Here, we show that TRAF6 E3 ubiquitin ligase and A20 deubiquitinase coordinate to regulate ATG9A ubiquitination and autophagy activation in cells responding to oxidative stress. The ROS-dependent TRAF6-mediated non-proteolytic, K48/63-linked ubiquitination of ATG9A enhances its association with Beclin 1 and the assembly of VPS34-UVRAG complex, thereby stimulating autophagy. Notably, expression of the ATG9A ubiquitination mutants impairs ROS-induced VPS34 activation and autophagy. We further find that lipopolysaccharide (LPS)-induced ROS production also stimulates TRAF6-mediated ATG9A ubiquitination. Ablation of ATG9A causes aberrant TLR4 endosomal trafficking and decreases IRF-3 phosphorylation in LPS-stimulated macrophages. Our findings provide important insights into how K48/K63-linked ubiquitination of ATG9A contributes to the regulation of oxidative stress-induced autophagy. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/595887 | ISSN: | 22111247 | DOI: | 10.1016/j.celrep.2022.110354 |
顯示於: | 分子醫學研究所 |
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