title: Intranuclear degradation of polyglutamine aggregates by the ubiquitin-proteasome system.
abstract: 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.
authors.affiliation: 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.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwata
authors.forename: Yu
authors.initials: Y
authors.lastname: Nagashima
authors.forename: Lumine
authors.initials: L
authors.lastname: Matsumoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yamanaka
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Date
authors.forename: Ken
authors.initials: K
authors.lastname: Deoka
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
mesh_terms: 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
chemical_list: 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