Homeostatic Levels of p62 Control Cytoplasmic Inclusion Body Formation in Autophagy-Deficient Mice

Masaaki Komatsu, Satoshi Waguri, Masato Koike, Yu shin Sou, Takashi Ueno, Taichi Hara, Noboru Mizushima, Jun ichi Iwata, Junji Ezaki, Shigeo Murata, Jun Hamazaki, Yasumasa Nishito, Shun ichiro Iemura, Tohru Natsume, Toru Yanagawa, Junya Uwayama, Eiji Warabi, Hiroshi Yoshida, Tetsuro Ishii, Akira KobayashiMasayuki Yamamoto, Zhenyu Yue, Yasuo Uchiyama, Eiki Kominami, Keiji Tanaka*

*この研究の対応する著者

研究成果: Article査読

1582 被引用数 (Scopus)

抄録

Inactivation of constitutive autophagy results in formation of cytoplasmic protein inclusions and leads to liver injury and neurodegeneration, but the details of abnormalities related to impaired autophagy are largely unknown. Here we used mouse genetic analyses to define the roles of autophagy in the aforementioned events. We report that the ubiquitin- and LC3-binding protein "p62" regulates the formation of protein aggregates and is removed by autophagy. Thus, genetic ablation of p62 suppressed the appearance of ubiquitin-positive protein aggregates in hepatocytes and neurons, indicating that p62 plays an important role in inclusion body formation. Moreover, loss of p62 markedly attenuated liver injury caused by autophagy deficiency, whereas it had little effect on neuronal degeneration. Our findings highlight the unexpected role of homeostatic level of p62, which is regulated by autophagy, in controlling intracellular inclusion body formation, and indicate that the pathologic process associated with autophagic deficiency is cell-type specific.

本文言語English
ページ(範囲)1149-1163
ページ数15
ジャーナルCell
131
6
DOI
出版ステータスPublished - 2007 12 14
外部発表はい

ASJC Scopus subject areas

  • 生化学、遺伝学、分子生物学(全般)

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