title: The autophagy pathway maintained signaling crosstalk with the Keap1-Nrf2 system through p62 in auditory cells under oxidative stress.
abstract: The main purposes of our study were to consider the effect of autophagy on auditory cells under oxidative stress, and the function of possible crosstalk among p62, Keap1 and Nrf2 in autophagy-deficient auditory cells. First, we described how cell death was induced in auditory cell line (HEI-OC1) exposed to H2O2. We found that the decision for the cell death of auditory cells under oxidative stress depends on the balance between autophagy and necrosis due to ATP depletion, and autophagy plays a cytoprotective function in oxidative stress-induced necrosis. Our data clearly suggested that autophagy was a cell survival mechanism in H2O2-induced cell death, based on the observation that suppression of autophagy by knockdown of Atg7 sensitized, whereas activation of autophagy by rapamycin protected against H2O2-induced cell death. Next, our results regarding the relationship among p62, Nrf2 and Keap1 by siRNA paradoxically showed that p62 creates a positive feedback loop in the Keap1/Nrf2 pathway. Autophagy impaired by Atg7 knockdown degrades Keap1 in a p62-dependent manner, whereas Nrf2 is activated. As a result, the cell death induced by H2O2 was promoted in auditory cells. Taken together, these results suggested that the autophagy pathway maintained signaling crosstalk with the Keap1-Nrf2 system through p62 in auditory cells under oxidative stress.
authors.affiliation: Department of Otolaryngology, Kamio Memorial Hospital, Tokyo 101-0063, Japan; Department of Otolaryngology, School of Medicine, Keio University, Tokyo 160-8582, Japan. Electronic address: ken.hayashi@jcom.home.ne.jp.
authors.forename: Ken
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Collaborative Research Resources, Core Instrumentation Facility, Keio University, Tokyo 160-8582, Japan. Electronic address: katsudanmrw@yahoo.co.jp.
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Dan
authors.affiliation: Department of Otolaryngology, School of Medicine, Keio University, Tokyo 160-8582, Japan. Electronic address: amifumi@gmail.com.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Goto
authors.affiliation: Department of Otolaryngology, School of Medicine, Keio University, Tokyo 160-8582, Japan; Department of Otolaryngology, School of Medicine, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: nanaakagi0707@yahoo.co.jp.
authors.forename: Nana
authors.initials: N
authors.lastname: Tshuchihashi
authors.affiliation: Department of Otolaryngology, School of Medicine, Nihon University, Tokyo 173-8610, Japan. Electronic address: nomusan@siren.ocn.ne.jp.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nomura
authors.affiliation: Department of Otolaryngology, School of Medicine, Keio University, Tokyo 160-8582, Japan. Electronic address: masato@2002.jukuin.keio.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Fujioka
authors.affiliation: Department of Otolaryngology, School of Medicine, Keio University, Tokyo 160-8582, Japan. Electronic address: shokanza@gmail.com.
authors.forename: Sho
authors.initials: S
authors.lastname: Kanzaki
authors.affiliation: Department of Otolaryngology, School of Medicine, Keio University, Tokyo 160-8582, Japan. Electronic address: ogawak@a5.keio.jp.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ogawa
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D000071193:Autophagy-Related Protein 7; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; C118585:P62 protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D020123:Sirolimus
keywords: Auditory cell; Autophagy; Keap1/Nrf2; Oxidative stress; p62