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Published online 6 February 2006. doi:10.1083/jcb.200505079
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 4, 497-504
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 A novel GTPase, CRAG, mediates promyelocytic leukemia protein–associated nuclear body formation and degradation of expanded polyglutamine protein

Qingyu Qin1,2, Ryoko Inatome1,2, Azusa Hotta1,2, Masaki Kojima1, Hirohei Yamamura2, Hirokazu Hirai3,4, Toshihiro Yoshizawa5, Hirofumi Tanaka6, Kiyoko Fukami6, and Shigeru Yanagi1,4

1 Laboratory of Molecular Biochemistry and 6 Laboratory of Genome and Biosignal, School of Life Science, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo 192-0392, Japan
2 Division of Proteomics, Department of Genome Science, Graduate School of Medicine, Kobe University, Chuo-Ku, Kobe 650-0017, Japan
3 Adavanced Science Research Center, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan
4 Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
5 Department of Neurology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305-8575, Japan

Correspondence to S. Yanagi: syanagi{at}ls.toyaku.ac.jp


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.

Q. Qin and R. Inatome contributed equally to this paper.

Abbreviations used in this paper: CRAM, CRMP-associated molecule; CRMP, collapsin response mediator protein; DOX, doxycycline; DRG, dorsal root ganglion; GTPase, guanosine triphosphatase; MJD, Machado-Joseph disease; NI, nuclear inclusion; NLS, nuclear localization signal; PML, promyelocytic leukemia protein; polyQ, polyglutamine protein; RING, really interesting new gene; ROS, reactive oxygen species; siRNA, small interfering RNA; WT, wild type.


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