Tsou Wei-Ling, Ouyang Michelle, Hosking Ryan R, Sutton Joanna R, Blount Jessica R, Burr Aaron A, Todi Sokol V
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA; Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Neurobiol Dis. 2015 Oct;82:12-21. doi: 10.1016/j.nbd.2015.05.010. Epub 2015 May 22.
Ataxin-3 is a deubiquitinase and polyglutamine (polyQ) disease protein with a protective role in Drosophila melanogaster models of neurodegeneration. In the fruit fly, wild-type ataxin-3 suppresses toxicity from several polyQ disease proteins, including a pathogenic version of itself that causes spinocerebellar ataxia type 3 and pathogenic huntingtin, which causes Huntington's disease. The molecular partners of ataxin-3 in this protective function are unclear. Here, we report that ataxin-3 requires its direct interaction with the ubiquitin-binding and proteasome-associated protein, Rad23 (known as hHR23A/B in mammals) in order to suppress toxicity from polyQ species in Drosophila. According to additional studies, ataxin-3 does not rely on autophagy or the proteasome to suppress polyQ-dependent toxicity in fly eyes. Instead this deubiquitinase, through its interaction with Rad23, leads to increased protein levels of the co-chaperone DnaJ-1 and depends on it to protect against degeneration. Through DnaJ-1, our data connect ataxin-3 and Rad23 to protective processes involved with protein folding rather than increased turnover of toxic polyQ species.
Ataxin-3是一种去泛素化酶和多聚谷氨酰胺（polyQ）疾病蛋白，在果蝇神经退行性疾病模型中具有保护作用。在果蝇中，野生型Ataxin-3可抑制多种polyQ疾病蛋白的毒性，包括其自身的致病版本（可导致3型脊髓小脑共济失调）以及致病的亨廷顿蛋白（可导致亨廷顿舞蹈症）。Ataxin-3在这种保护功能中的分子伴侣尚不清楚。在此，我们报告Ataxin-3需要与泛素结合及蛋白酶体相关蛋白Rad23（在哺乳动物中称为hHR23A/B）直接相互作用，才能抑制果蝇中polyQ物种的毒性。根据其他研究，Ataxin-3并不依赖自噬或蛋白酶体来抑制果蝇眼睛中polyQ依赖性毒性。相反，这种去泛素化酶通过与Rad23相互作用，导致共伴侣蛋白DnaJ-1的蛋白质水平升高，并依赖它来防止退化。通过DnaJ-1，我们的数据将Ataxin-3和Rad23与涉及蛋白质折叠的保护过程联系起来，而不是与有毒polyQ物种的周转增加联系起来。
