A novel GTPase, CRAG, mediates promyelocytic leukemia protein–associated nuclear body formation and degradation of expanded polyglutamine protein

• DOI: 10.1083/jcb.200505079
• Publication Date: 2006-02-07T01:24:20Z
• Authors: Qingyu Qin; Ryoko Inatome; Azusa Hotta; Masaki Kojima; Hirohei Yamamura; Hirokazu Hirai; Toshihiro Yoshizawa; Hirofumi Tanaka; Kiyoko Fukami; Shigeru Yanagi
• Keywords: 0303 health sciences; Tumor Suppressor Proteins; Intranuclear Inclusion Bodies; Molecular Sequence Data; Nuclear Localization Signals; Autophagy-Related Proteins; Nuclear Proteins; Ubiquitin-Activating Enzymes; Promyelocytic Leukemia Protein; Autophagy-Related Protein 7; GTP Phosphohydrolases; Neoplasm Proteins; Rats; Mice; 03 medical and health sciences; Animals; Humans; Amino Acid Sequence; Peptides; Research Articles; Cells, Cultured; HeLa Cells; Transcription Factors

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.