title: Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy.
abstract: The Keap1-Nrf2 system and autophagy are both involved in the oxidative-stress response, metabolic pathways, and innate immunity, and dysregulation of these processes is associated with pathogenic processes. However, the interplay between these two pathways remains largely unknown. Here, we show that phosphorylation of the autophagy-adaptor protein p62 markedly increases p62's binding affinity for Keap1, an adaptor of the Cul3-ubiquitin E3 ligase complex responsible for degrading Nrf2. Thus, p62 phosphorylation induces expression of cytoprotective Nrf2 targets. p62 is assembled on selective autophagic cargos such as ubiquitinated organelles and subsequently phosphorylated in an mTORC1-dependent manner, implying coupling of the Keap1-Nrf2 system to autophagy. Furthermore, persistent activation of Nrf2 through accumulation of phosphorylated p62 contributes to the growth of human hepatocellular carcinomas (HCCs). These results demonstrate that selective autophagy and the Keap1-Nrf2 pathway are interdependent, and that inhibitors of the interaction between phosphorylated p62 and Keap1 have potential as therapeutic agents against human HCC.
authors.affiliation: Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Ichimura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Waguri
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Sou
authors.forename: Shun
authors.initials: S
authors.lastname: Kageyama
authors.forename: Jun
authors.initials: J
authors.lastname: Hasegawa
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Ishimura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Saito
authors.forename: Yinjie
authors.initials: Y
authors.lastname: Yang
authors.forename: Tsuguka
authors.initials: T
authors.lastname: Kouno
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukutomi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hoshii
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.forename: Kenji
authors.initials: K
authors.lastname: Takagi
authors.forename: Tsunehiro
authors.initials: T
authors.lastname: Mizushima
authors.forename: Hozumi
authors.initials: H
authors.lastname: Motohashi
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yoshimori
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism*; D000236:Adenoma / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010766:Phosphorylation; D000071456:Sequestosome-1 Protein; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D006360:Heat-Shock Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D046912:Multiprotein Complexes; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases