Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice.
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.
Komatsu
Masaaki
M
Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan.
Waguri
Satoshi
S
Koike
Masato
M
Sou
Yu-Shin
YS
Ueno
Takashi
T
Hara
Taichi
T
Mizushima
Noboru
N
Iwata
Jun-Ichi
J
Ezaki
Junji
J
Murata
Shigeo
S
Hamazaki
Jun
J
Nishito
Yasumasa
Y
Iemura
Shun-Ichiro
S
Natsume
Tohru
T
Yanagawa
Toru
T
Uwayama
Junya
J
Warabi
Eiji
E
Yoshida
Hiroshi
H
Ishii
Tetsuro
T
Kobayashi
Akira
A
Yamamoto
Masayuki
M
Yue
Zhenyu
Z
Uchiyama
Yasuo
Y
Kominami
Eiki
E
Tanaka
Keiji
K
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
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