title: A novel GTPase, CRAG, mediates promyelocytic leukemia protein-associated nuclear body formation and degradation of expanded polyglutamine protein.
abstract: Polyglutamine diseases are inherited neurodegenerative diseases caused by the expanded polyglutamine proteins (polyQs). We have identified a novel guanosine triphosphatase (GTPase) named CRAG that contains a nuclear localization signal (NLS) sequence and forms nuclear inclusions in response to stress. After ultraviolet irradiation, CRAG interacted with and induced an enlarged ring-like structure of promyelocytic leukemia protein (PML) body in a GTPase-dependent manner. Reactive oxygen species (ROS) generated by polyQ accumulation triggered the association of CRAG with polyQ and the nuclear translocation of the CRAG-polyQ complex. Furthermore, CRAG promoted the degradation of polyQ at PML/CRAG bodies through the ubiquitin-proteasome pathway. CRAG knockdown by small interfering RNA in neuronal cells consistently blocked the nuclear translocation of polyQ and enhanced polyQ-mediated cell death. We propose that CRAG is a modulator of PML function and dynamics in ROS signaling and is protectively involved in the pathogenesis of polyglutamine diseases.
authors.affiliation: Laboratory of Molecular Biochemistry and 6Laboratory of Genome and Biosignal, School of Life Science, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Qin
authors.forename: Ryoko
authors.initials: R
authors.lastname: Inatome
authors.forename: Azusa
authors.initials: A
authors.lastname: Hotta
authors.forename: Masaki
authors.initials: M
authors.lastname: Kojima
authors.forename: Hirohei
authors.initials: H
authors.lastname: Yamamura
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hirai
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Yoshizawa
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Fukami
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yanagi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D002478:Cells, Cultured; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D000071183:Autophagy-Related Proteins; D009363:Neoplasm Proteins; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D010455:Peptides; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C097188:polyglutamine; D044763:Ubiquitin-Conjugating Enzymes; D020558:GTP Phosphohydrolases; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; C455621:ATG3 protein, human