Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23.
Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23.
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DOI：
10.1038/ncomms5638
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发表时间：
2014-08-21
影响因子：
16.6
通讯作者：
Todi, Sokol V.
中科院分区：
文献类型：
--
作者：
Blount, Jessica R.;Tsou, Wei-Ling;Ristic, Gorica;Burr, Aaron A.;Ouyang, Michelle;Galante, Holland;Scaglione, K. Matthew;Todi, Sokol V.
共济失调蛋白-3中的多聚谷氨酰胺重复扩增导致最常见的显性共济失调，脊髓小脑共济失调3型（SCA 3）的神经变性。由于降低疾病蛋白的水平可以改善动物的病理学，我们研究了共济失调蛋白-3是如何降解的。在这里，我们表明，与大多数蛋白质，共济失调蛋白3营业额不需要它的泛素化，但它的N端的泛素结合位点2（UbS 2）的调节。突变UbS 2通过增加其蛋白酶体周转来降低培养的哺乳动物细胞和果蝇中的共济失调蛋白-3蛋白水平。共济失调蛋白-3通过UbS 2与蛋白酶体相关蛋白Rad 23 A/B相互作用。在培养细胞和果蝇中敲低Rad 23导致共济失调蛋白-3水平降低。重要的是，减少Rad 23抑制了果蝇中的共济失调蛋白-3依赖性变性。我们提出了一种泛素化不依赖性降解的机制，这种机制受到蛋白质与蛋白酶体相关因子相互作用的阻碍。我们的结论是，UbS 2是一个潜在的目标，通过它来增强共济失调蛋白-3降解SCA 3治疗。
Polyglutamine repeat expansion in ataxin-3 causes neurodegeneration in the most common dominant ataxia, Spinocerebellar Ataxia Type 3 (SCA3). Since reducing levels of disease proteins improves pathology in animals, we investigated how ataxin-3 is degraded. Here we show that, unlike most proteins, ataxin-3 turnover does not require its ubiquitination, but is regulated by Ubiquitin-Binding Site 2 (UbS2) on its N terminus. Mutating UbS2 decreases ataxin-3 protein levels in cultured mammalian cells and in Drosophila melanogaster by increasing its proteasomal turnover. Ataxin-3 interacts with the proteasome-associated proteins Rad23A/B through UbS2. Knockdown of Rad23 in cultured cells and in Drosophila results in lower levels of ataxin-3 protein. Importantly, reducing Rad23 suppresses ataxin-3-dependent degeneration in flies. We present a mechanism for ubiquitination-independent degradation that is impeded by protein interactions with proteasome-associated factors. We conclude that UbS2 is a potential target through which to enhance ataxin-3 degradation for SCA3 therapy.
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影响因子：
3.5
作者：
Alves, Sandro;Nascimento-Ferreira, Isabel;de Almeida, Luis Pereira
通讯作者：
de Almeida, Luis Pereira
DOI：
10.1073/pnas.0501507102
发表时间：
2005-04-19
影响因子：
11.1
作者：
Harper, SQ;Staber, PD;Davidson, BL
通讯作者：
Davidson, BL
影响因子：
4.8
作者：
Jana, NR;Dikshit, P;Nukina, N
通讯作者：
Nukina, N
影响因子：
3.5
作者：
Alves, Sandro;Regulier, Etienne;de Almeida, Luis Pereira
通讯作者：
de Almeida, Luis Pereira
影响因子：
6.7
作者：
Costa, Maria do Carmo;Paulson, Henry L.
通讯作者：
Paulson, Henry L.