title: The ER stress regulator Bip mediates cadmium-induced autophagy and neuronal senescence.
abstract: Autophagy is protective in cadmium (Cd)-induced oxidative damage. Endoplasmic reticulum (ER) stress has been shown to induce autophagy in a process requiring the unfolded protein response signalling pathways. Cd treatment significantly increased senescence in neuronal cells, which was aggravated by 3-MA or silencing of Atg5 and abolished by rapamycin. Cd increased expression of ER stress regulators Bip, chop, eIf2α, and ATF4, and activated autophagy as evidenced by upregulated LC3. Moreover, the ER stress inhibitor mithramycin inhibited the expression of ER stress protein chaperone Bip and blocked autophagic flux. Downregulating Bip significantly blocked the conversion of LC3-I to LC3-II, decreased LC3 puncta formation, and prevented the increase of senescence in PC12 cells. Interestingly, knocking down Bip regulated the expression of p-AMPK, p-AKT and p-s6k induced by Cd. BAPTA, a Bip inhibitor, decreased the expression of p-AMPK and LC3-II, but enhanced neuronal senescence. In addition, we found that siRNA for Bip enhanced GATA4 expression after 6 h Cd exposure in PC12 cells, while rapamycin treatment decreased GATA4 levels induced by 24 h Cd exposure. These results indicate that autophagy degraded GATA4 in a Bip-dependent way. Our findings suggest that autophagy regulated by Bip expression after ER stress suppressed Cd-induced neuronal senescence.
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, PR China.|Jiangsu Key Laboratory of Zoonosis, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, PR China.|Jiangsu Key Laboratory of Zoonosis, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, PR China.|Jiangsu Key Laboratory of Zoonosis, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zou
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, PR China.|Jiangsu Key Laboratory of Zoonosis, China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Yang
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, PR China.|Jiangsu Key Laboratory of Zoonosis, China.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Zhao
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, PR China.|Jiangsu Key Laboratory of Zoonosis, China.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, PR China.|Jiangsu Key Laboratory of Zoonosis, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, PR China.|Jiangsu Key Laboratory of Zoonosis, China.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Bian
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, PR China.|Jiangsu Key Laboratory of Zoonosis, China.
authors.forename: Xuezhong
authors.initials: X
authors.lastname: Liu
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, PR China.|Jiangsu Key Laboratory of Zoonosis, China.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Gu
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, PR China.|Jiangsu Key Laboratory of Zoonosis, China.
authors.forename: Zongping
authors.initials: Z
authors.lastname: Liu
authors.affiliation: College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, PR China.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, PR China.|Jiangsu Key Laboratory of Zoonosis, China.
authors.forename: Jiaqiao
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001343:Autophagy; D002104:Cadmium / Q000009:adverse effects*; D016922:Cellular Senescence / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D002104:Cadmium; D050991:GATA4 Transcription Factor; D006360:Heat-Shock Proteins; D020123:Sirolimus; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C084365:Gata4 protein, rat