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

Hum Mol Genet. 2009 Sep 1;18(17):3334-43. doi: 10.1093/hmg/ddp274. Epub 2009 Jun 19.

Abstract

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 CK2alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-3
  • Casein Kinase II / genetics
  • Casein Kinase II / metabolism*
  • Cell Line
  • Cell Nucleus / chemistry
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Humans
  • Machado-Joseph Disease / genetics
  • Machado-Joseph Disease / metabolism*
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Protein Stability
  • Protein Transport
  • Rats
  • Repressor Proteins / chemistry*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*

Substances

  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • Casein Kinase II
  • ATXN3 protein, human
  • Ataxin-3
  • Atxn3 protein, rat