@article{ccf623f1428348fabd822b6984323468,
title = "The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1",
abstract = "Impaired selective turnover of p62 by autophagy causes severe liver injury accompanied by the formation of p62-positive inclusions and upregulation of detoxifying enzymes. These phenotypes correspond closely to the pathological conditions seen in human liver diseases, including alcoholic hepatitis and hepatocellular carcinoma. However, the molecular mechanisms and pathophysiological processes in these events are still unknown. Here we report the identification of a novel regulatory mechanism by p62 of the transcription factor Nrf2, whose target genes include antioxidant proteins and detoxification enzymes. p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2. Thus, an overproduction of p62 or a deficiency in autophagy competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and transcriptional activation of Nrf2 target genes. Our findings indicate that the pathological process associated with p62 accumulation results in hyperactivation of Nrf2 and delineates unexpected roles of selective autophagy in controlling the transcription of cellular defence enzyme genes.",
author = "Masaaki Komatsu and Hirofumi Kurokawa and Satoshi Waguri and Keiko Taguchi and Akira Kobayashi and Yoshinobu Ichimura and Sou, {Yu Shin} and Izumi Ueno and Ayako Sakamoto and Tong, {Kit I.} and Mihee Kim and Yasumasa Nishito and Iemura, {Shun Ichiro} and Tohru Natsume and Takashi Ueno and Eiki Kominami and Hozumi Motohashi and Keiji Tanaka and Masayuki Yamamoto",
note = "Funding Information: and A. Yabashi (Fukushima Medical University School of Medicine) for their help in histological studies; J. Yanagisawa (Tsukuba University) and Y. Saeki (Tokyo Metropolitan Institute of Medical Science) for mass spectrometric analyses; Y. Kawatani (Tohoku University) for technical assistance in microarray analyses; and R. Kopito and B. E. Riley (Stanford University) and T. Mizushima and T. Kumanomidou (Nagoya University) for helpful discussion. p62-knockout mice were provided by T. Ishii (Tsukuba University). The Biomedical Research Core of Tohoku University Graduate School of Medicine provided DRI-CHEM 7000V (Fuji Film Corp.). This work was supported by grants from the Japan Science and Technology Agency (M.K.), the Ministry of Education, Science and Culture of Japan (M.K., K.T. and M.Y.) and the Targeted Proteins Research Program (H.K., K.T. and M.Y.).",
year = "2010",
month = mar,
doi = "10.1038/ncb2021",
language = "English",
volume = "12",
pages = "213--223",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "3",
}