Human Molecular Genetics Advance Access published online on June 19, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp274
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CK2-Dependent Phosphorylation Determines Cellular Localization and Stability of Ataxin-3
Friedrich-Wilhelms-University Bonn, UKB, Department of Neurology, Sigmund-Freud-Str. 25, 53105 Bonn, Germany
* Corresponding authors: Ullrich Wüllner & Bernd O. Evert, Department of Neurology, Sigmund-Freud-Str. 25, 53105 Bonn, Germany phone: 0049 228 28715712; fax: 0049 228 28715024 email: wuellner{at}uni-bonn.de or b.evert{at}uni-bonn.de
Received March 27, 2009; Revised May 20, 2009; Accepted June 8, 2009
The nuclear presence of the expanded disease proteins is of critical importance for the pathogeneses of polyglutamine diseases. Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls the nuclear localization, aggregation, and stability of ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3). Serine 340 and 352 within the third ubiquitin-interacting motif of ATXN3 were particularly important for nuclear localization of normal and expanded ATXN3 and mutation of these sites robustly reduced the formation of nuclear inclusions; a putative nuclear leader sequence was not required. ATXN3 associated with CK2
and pharmacological inhibition of CK2 decreased nuclear ATXN3 levels and the formation of nuclear inclusions. Moreover, we found that ATXN3 shifted to the nucleus upon thermal stress in a CK2-dependent manner, indicating a key role of CK2-mediated phosphorylation of ATXN3 in SCA3 pathophysiology.