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Regulation of ER stress-induced autophagy by GSK3β-TIP60-ULK1 pathway. - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal Title:

Cell Death and Disease


Volume 7, Number 12


Nature Publishing Group: Open Access Journals - Option C | 2016-12-29, Pages e2563-e2563

Type of Work:

Article | Final Publisher PDF

Abstract: Endoplasmic reticulum ER stress is involved in many cellular processes. Emerging evidence suggests that ER stress can trigger autophagy; however, the mechanisms by which ER stress regulates autophagy and its role in this condition are not fully understood. HIV Tat-interactive protein, 60 kDa TIP60 is a newly discovered acetyltransferase that can modulate autophagy flux by activating ULK1 upon growth factor deprivation. In this study, we investigated the mechanisms by which ER stress induces autophagy. We showed that ER stress activates glycogen synthase kinase-3β GSK3β. This led to a GSK3β-dependent phosphorylation of TIP60, triggering a TIP60-mediated acetylation of ULK1 and activation of autophagy. Inhibition of either GSK3β or TIP60 acetylation activities significantly attenuated ER stress-induced autophagy. Moreover, enhancing the level of TIP60 attenuated the level of CHOP after ER stress, and reduced the ER stress-induced cell death. In contrast, expression of TIP60 mutant that could not be phosphorylated by GSK3β exacerbated the generation of CHOP and increased the ER stress-induced cell death. These findings reveal that ER stress engages the GSK3β-TIP60-ULK1 pathway to increase autophagy. Attenuation of this pathway renders cells more sensitive to and increases the toxicity of ER stress.

Subjects: Health Sciences, Pharmacology - Health Sciences, General - Research Funding: This work was supported by the National Natural Science Foundation of China, Grant No. 31371400 to QY and the State Key Laboratory of Neuroscience, Grant No. SKLN-2015B03 to QY.

Keywords: Endoplasmic Reticulum ER - autophagy - Tunicamycin -

Autor: Tiejian Nie, Shaosong Yang, Hongwei Ma, Lei Zhang, Fangfang Lu, Kai Tao, Ronglin Wang, Ruixin Yang, Lu Huang, Zixu Mao, Qian Yang



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