Proteotoxic stress increases nuclear localization of ataxin-3

Hum Mol Genet. 2010 Jan 15;19(2):235-49. doi: 10.1093/hmg/ddp482. Epub 2009 Oct 19.


Spinocerebellar ataxia type 3 (SCA3)/Machado Joseph disease results from expansion of the polyglutamine domain in ataxin-3 (Atx3). Atx3 is a transcriptional co-repressor, as well as a deubiquitinating enzyme that appears to function in cellular pathways involved in protein homeostasis. In this study, we show that interactions of Atx3 with valosin-containing protein and hHR23B are dynamic and modulated by proteotoxic stresses. Heat shock, a general proteotoxic stress, also induced wild-type and pathogenic Atx3 to accumulate in the nucleus. Mapping studies showed that two regions of Atx3, the Josephin domain and the C-terminus, regulated heat shock-induced nuclear localization. Heat shock-induced nuclear localization of Atx3 was not affected by a casein kinase-2 inhibitor or by mutating a predicted nuclear localization signal. However, serine-111 of Atx3 was required for nuclear localization of the Josephin domain and regulated nuclear localization of full-length Atx3. Atx3 null cells were more sensitive to toxic effects of heat shock suggesting that Atx3 had a protective function in the cellular response to heat shock. Importantly, we found that oxidative stress also induced nuclear localization of Atx3; both wild-type and pathogenic Atx3 accumulated in the nucleus of SCA3 patient fibroblasts following oxidative stress. Heat shock and oxidative stress are the first processes identified that increase nuclear localization of Atx3. Observations in this study provide new and important insights for understanding SCA3 pathology as the nucleus is likely a key site for early pathogenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Ataxin-3
  • Cell Line
  • Cell Nucleus / chemistry
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Fibroblasts / chemistry
  • Fibroblasts / metabolism
  • Heat-Shock Response*
  • Humans
  • Machado-Joseph Disease / genetics
  • Machado-Joseph Disease / metabolism
  • Machado-Joseph Disease / physiopathology*
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oxidative Stress
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Transport
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*


  • DNA-Binding Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RAD23B protein, human
  • Repressor Proteins
  • ATXN3 protein, human
  • Ataxin-3
  • DNA Repair Enzymes