Proteotoxic stress increases nuclear localization of ataxin-3
- 19 October 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 19 (2), 235-249
- https://doi.org/10.1093/hmg/ddp482
Abstract
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.Keywords
This publication has 65 references indexed in Scilit:
- Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulationNeurobiology of Disease, 2008
- Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and agingGenes & Development, 2008
- Adapting Proteostasis for Disease InterventionScience, 2008
- Oxidative stress in neurodegeneration in dentatorubral-pallidoluysian atrophyJournal of the Neurological Sciences, 2008
- Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cellsProceedings of the National Academy of Sciences of the United States of America, 1999
- Nuclear Targeting of Mutant Huntingtin Increases ToxicityMolecular and Cellular Neuroscience, 1999
- Evidence for Proteasome Involvement in Polyglutamine Disease: Localization to Nuclear Inclusions in SCA3/MJD and Suppression of Polyglutamine Aggregation in vitroHuman Molecular Genetics, 1999
- A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES maskingThe EMBO Journal, 1999
- Recruitment and the Role of Nuclear Localization in Polyglutamine-mediated AggregationThe Journal of cell biology, 1998
- Heterogeneous Intracellular Localization and Expression of Ataxin-3Neurobiology of Disease, 1998