Intranuclear degradation of polyglutamine aggregates by the ubiquitin-proteasome system.
Huntington disease and its related autosomal-dominant polyglutamine (pQ) neurodegenerative diseases are characterized by intraneuronal accumulation of protein aggregates. Studies on protein aggregates have revealed the importance of the ubiquitin-proteasome system as the front line of protein quality control (PQC) machinery against aberrant proteins. Recently, we have shown that the autophagy-lysosomal system is also involved in cytoplasmic aggregate degradation, but the nucleus lacked this activity. Consequently, the nucleus relies entirely on the ubiquitin-proteasome system for PQC. According to previous studies, nuclear aggregates possess a higher cellular toxicity than do their cytoplasmic counterparts, however degradation kinetics of nuclear aggregates have been poorly understood. Here we show that nuclear ubiquitin ligases San1p and UHRF-2 each enhance nuclear pQ aggregate degradation and rescued pQ-induced cytotoxicity in cultured cells and primary neurons. Moreover, UHRF-2 is associated with nuclear inclusion bodies in vitro and in vivo. Our data suggest that UHRF-2 is an essential molecule for nuclear pQ degradation as a component of nuclear PQC machinery in mammalian cells.
Iwata
Atsushi
A
Departments of Molecular Neuroscience on Neurodegeneration and Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Nagashima
Yu
Y
Matsumoto
Lumine
L
Suzuki
Takahiro
T
Yamanaka
Tomoyuki
T
Date
Hidetoshi
H
Deoka
Ken
K
Nukina
Nobuyuki
N
Tsuji
Shoji
S
D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D010455:Peptides; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; C097188:polyglutamine; C500396:SAN1 protein, S cerevisiae; C465619:UHRF2 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex