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PDBsum entry 3ade
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Transcription
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PDB id
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3ade
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References listed in PDB file
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Key reference
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Title
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The selective autophagy substrate p62 activates the stress responsive transcription factor nrf2 through inactivation of keap1.
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Authors
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M.Komatsu,
H.Kurokawa,
S.Waguri,
K.Taguchi,
A.Kobayashi,
Y.Ichimura,
Y.S.Sou,
I.Ueno,
A.Sakamoto,
K.I.Tong,
M.Kim,
Y.Nishito,
S.Iemura,
T.Natsume,
T.Ueno,
E.Kominami,
H.Motohashi,
K.Tanaka,
M.Yamamoto.
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Ref.
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Nat Cell Biol, 2010,
12,
213-223.
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PubMed id
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Abstract
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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.
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