Journal Article

The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1

Taguchi, Keiko, Yamamoto, Masayuki, Ueno, Izumi, Tong, Kit I., Waguri, Satoshi, Ueno, Takashi, Nishito, Yasumasa, Sakamoto, Ayako, Sou, Yu-Shin, Kurokawa, Hirofumi, Tanaka, Keiji, Kobayashi, Akira, Iemura, Shun-ichiro, Kim, Mihee, Motohashi, Hozumi, Komatsu, Masaaki, Kominami, Eiki, Ichimura, Yoshinobu, Natsume, Tohru

2010

Overview

Impaired turnover of the autophagy substrate p62 leads to liver injury. p62 inhibits the ubiquitin ligase Keap1, leading to stabilization of the transcription factor Nrf2. High levels of p62 in autophagy deficient animals leads to unusually high expression of Nrf2 targets genes and results in liver injury. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/45/612/822 / 631/80/82/39 / Adaptor Proteins, Signal Transducing - chemistry / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Amino acids / Animals / Antibodies / Antioxidants / Autophagy / Autophagy (Cytology) / Autophagy - physiology / Autophagy-Related Protein 7 / Binding, Competitive - physiology / Biochemistry / Biomedical and Life Sciences / Calorimetry / Cancer Research / Care and treatment / Cell Biology / Cell Line / Crystallography, X-Ray / Cytoskeletal Proteins - chemistry / Cytoskeletal Proteins - genetics / Cytoskeletal Proteins - metabolism / Detoxification / Developmental Biology / Enzymes / Gene Expression - genetics / Genetic aspects / Heat-Shock Proteins - chemistry / Heat-Shock Proteins - genetics / Heat-Shock Proteins - metabolism / Hepatitis / Hepatocytes - metabolism / Hepatocytes - pathology / Humans / Inactivation / Inclusion Bodies - metabolism / Intracellular Signaling Peptides and Proteins - metabolism / Kelch-Like ECH-Associated Protein 1 / Life Sciences / Liver / Liver - metabolism / Liver - pathology / Liver - physiopathology / Liver cancer / Liver diseases / Mice / Mice, Knockout / Mice, Transgenic / Microtubule-Associated Proteins - genetics / Models, Biological / Models, Molecular / Mutation - physiology / NF-E2-Related Factor 2 - genetics / NF-E2-Related Factor 2 - metabolism / Organ Size - genetics / Oxidative Stress - physiology / Physiological aspects / Protein Binding - physiology / Protein Interaction Domains and Motifs - physiology / Protein Interaction Mapping / Proteins / Sequestosome-1 Protein / Signal Transduction - physiology / Stem Cells / Transcription factors / Transfection