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

Research output: Contribution to journalArticle

1445 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1149-1163
Number of pages15
JournalCell
Volume131
Issue number6
DOIs
Publication statusPublished - 2007 Dec 14

Keywords

  • CELLBIO
  • HUMDISEASE
  • PROTEINS

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Komatsu, M., Waguri, S., Koike, M., Sou, Y. S., Ueno, T., Hara, T., Mizushima, N., Iwata, J. I., Ezaki, J., Murata, S., Hamazaki, J., Nishito, Y., Iemura, S. I., Natsume, T., Yanagawa, T., Uwayama, J., Warabi, E., Yoshida, H., Ishii, T., ... Tanaka, K. (2007). Homeostatic Levels of p62 Control Cytoplasmic Inclusion Body Formation in Autophagy-Deficient Mice. Cell, 131(6), 1149-1163. https://doi.org/10.1016/j.cell.2007.10.035