title: Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice.
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.
authors: Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan.
authors: Masaaki
authors: M
authors: Komatsu
authors: Satoshi
authors: S
authors: Waguri
authors: Masato
authors: M
authors: Koike
authors: Yu-Shin
authors: YS
authors: Sou
authors: Takashi
authors: T
authors: Ueno
authors: Taichi
authors: T
authors: Hara
authors: Noboru
authors: N
authors: Mizushima
authors: Jun-Ichi
authors: J
authors: Iwata
authors: Junji
authors: J
authors: Ezaki
authors: Shigeo
authors: S
authors: Murata
authors: Jun
authors: J
authors: Hamazaki
authors: Yasumasa
authors: Y
authors: Nishito
authors: Shun-Ichiro
authors: S
authors: Iemura
authors: Tohru
authors: T
authors: Natsume
authors: Toru
authors: T
authors: Yanagawa
authors: Junya
authors: J
authors: Uwayama
authors: Eiji
authors: E
authors: Warabi
authors: Hiroshi
authors: H
authors: Yoshida
authors: Tetsuro
authors: T
authors: Ishii
authors: Akira
authors: A
authors: Kobayashi
authors: Masayuki
authors: M
authors: Yamamoto
authors: Zhenyu
authors: Z
authors: Yue
authors: Yasuo
authors: Y
authors: Uchiyama
authors: Eiki
authors: E
authors: Kominami
authors: Keiji
authors: K
authors: Tanaka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D001921:Brain / Q000201:enzymology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D002479:Inclusion Bodies / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse