Proteotoxic stress increases nuclear localization of ataxin-3

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.

Valosin-containing Protein (VCP) in Novel Feedback Machinery between Abnormal Protein Accumulation and Transcriptional Suppression

“…Recently, Reina et al demonstrated that MJD protein/ataxin 3 translocated into the nucleus immediately after the heat shock. In this condition, VCP appeared to stay in the cytoplasm (48). It would also be interesting to see whether histone deacetylation could be observed after the heat shock.…”

Deubiquitylases From Genes to Organism

“…However, there is a general elevation in the amount of ubiquitylated protein (229). ATXN3 regulates transcription of multiple genes (65,215), a property which may allow for a coordinated response to proteotoxic stresses, which have been shown to promote nuclear accummulation of ATXN3 (206). In C. elegans, ATXN3 has been linked to the control of longevity by the IGF-I signaling axis (131).…”

Activity and Cellular Functions of the Deubiquitinating Enzyme and Polyglutamine Disease Protein Ataxin-3 Are Regulated by Ubiquitination at Lysine 117

“…In Drosophila, AT3 suppresses poly(Q)-induced neurodegeneration in a catalytic activity-dependent manner (20). Atxn3 knock-out mouse embryonic fibroblasts (MEFs) are more sensitive than wild type MEFs to heat shock (21). In cells, AT3 assists in the proteasomal targeting of endoplasmic reticulum-associated degradation substrates (22,23) and induces aggresome formation (24).…”