The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1.
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.
Komatsu
Masaaki
M
Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan. komatsu-ms@igakuken.or.jp
Kurokawa
Hirofumi
H
Waguri
Satoshi
S
Taguchi
Keiko
K
Kobayashi
Akira
A
Ichimura
Yoshinobu
Y
Sou
Yu-Shin
YS
Ueno
Izumi
I
Sakamoto
Ayako
A
Tong
Kit I
KI
Kim
Mihee
M
Nishito
Yasumasa
Y
Iemura
Shun-ichiro
S
Natsume
Tohru
T
Ueno
Takashi
T
Kominami
Eiki
E
Motohashi
Hozumi
H
Tanaka
Keiji
K
Yamamoto
Masayuki
M
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D001667:Binding, Competitive / Q000502:physiology; D002151:Calorimetry; D002460:Cell Line; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation / Q000502:physiology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D025941:Protein Interaction Mapping; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; C502661:Atg7 protein, mouse; D003598:Cytoskeletal Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D000071193:Autophagy-Related Protein 7