title: Regulation of ER stress-induced autophagy by GSK3β-TIP60-ULK1 pathway.
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.
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, 569 Xinsi Road, Xi'an, Shaanxi 710038, China.
authors.forename: Tiejian
authors.initials: T
authors.lastname: Nie
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, 569 Xinsi Road, Xi'an, Shaanxi 710038, China.
authors.forename: Shaosong
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Microbiology, Faculty of Preclinical Medicine, The Fourth Military Medical University, 169 Changlexi Road, Xi'an, Shaanxi 710032, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, 569 Xinsi Road, Xi'an, Shaanxi 710038, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, 569 Xinsi Road, Xi'an, Shaanxi 710038, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Lu
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, 569 Xinsi Road, Xi'an, Shaanxi 710038, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Tao
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, 569 Xinsi Road, Xi'an, Shaanxi 710038, China.
authors.forename: Ronglin
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, 569 Xinsi Road, Xi'an, Shaanxi 710038, China.
authors.forename: Ruixin
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, 569 Xinsi Road, Xi'an, Shaanxi 710038, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and Neurology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
authors.forename: Zixu
authors.initials: Z
authors.lastname: Mao
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, 569 Xinsi Road, Xi'an, Shaanxi 710038, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D000071189:Autophagy-Related Protein-1 Homolog / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000074443:Lysine Acetyltransferase 5; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D006861:Hydrogen Peroxide; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D000071189:Autophagy-Related Protein-1 Homolog; D000071679:Glycogen Synthase Kinase 3 beta; C484754:ULK1 protein, human