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PDBsum entry 3wdz
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Transcription
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PDB id
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3wdz
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References listed in PDB file
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Key reference
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Title
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Phosphorylation of p62 activates the keap1-Nrf2 pathway during selective autophagy.
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Authors
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Y.Ichimura,
S.Waguri,
Y.S.Sou,
S.Kageyama,
J.Hasegawa,
R.Ishimura,
T.Saito,
Y.Yang,
T.Kouno,
T.Fukutomi,
T.Hoshii,
A.Hirao,
K.Takagi,
T.Mizushima,
H.Motohashi,
M.S.Lee,
T.Yoshimori,
K.Tanaka,
M.Yamamoto,
M.Komatsu.
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Ref.
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Mol Cell, 2013,
51,
618-631.
[DOI no: ]
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PubMed id
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Abstract
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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.
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