Journal Article

CK2-dependent phosphorylation determines cellular localization and stability of ataxin-3

Thorsten Mueller, Peter Breuer, Ina Schmitt, Jochen Walter, Bernd O. Evert and Ullrich Wüllner

in Human Molecular Genetics

Volume 18, issue 17, pages 3334-3343
Published in print September 2009 | ISSN: 0964-6906
Published online June 2009 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddp274
CK2-dependent phosphorylation determines cellular localization and stability of ataxin-3

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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 CK2α 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.

Journal Article.  6068 words.  Illustrated.

Subjects: Genetics and Genomics

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