Ubiquitin-specific protease 14 modulates degradation of cellular prion protein.
Ubiquitin-specific protease 14 modulates degradation of cellular prion protein.
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DOI：
10.1038/srep11028
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发表时间：
2015-06-10
影响因子：
4.6
通讯作者：
Nishida N
中科院分区：
文献类型：
--
作者：
Homma T;Ishibashi D;Nakagaki T;Fuse T;Mori T;Satoh K;Atarashi R;Nishida N
朊病毒疾病是以朊蛋白（PrPC）积累为特征的致死性神经退行性疾病。迄今为止，对这种疾病还没有有效的治疗方法。累积的PrP称为PrPSc，形成淀粉样原纤维，可能具有传染性。有研究表明，PrPSc异常折叠并抵抗蛋白水解降解，并且还抑制受感染细胞的蛋白酶体功能，从而诱导神经元死亡。最近的研究表明，泛素-蛋白酶体系统参与了PrPC的质量控制。为了揭示朊蛋白泛素化的意义，我们重点研究了泛素特异性蛋白酶14 (USP14)，这是一种去泛素化酶，可以催化多泛素链的修剪，并在蛋白酶体过程中发挥作用。本研究的结果表明，使用选择性USP14抑制剂治疗可降低朊病毒感染的神经元细胞中PrPC和PrPSc的水平。在朊病毒感染的细胞中，USP14显性阴性突变体的过表达降低了PrPSc，而野生型USP14则增加了PrPSc。这些结果表明，USP14可以阻止正常和异常PrP的降解。总之，更好地了解USP14引起的PrPSc清除的调控可能有助于开发朊病毒疾病的治疗策略。
Prion diseases are fatal neurodegenerative disorders characterized by the accumulation of prion protein (PrPC). To date, there is no effective treatment for the disease. The accumulated PrP, termed PrPSc, forms amyloid fibrils and could be infectious. It has been suggested that PrPSc is abnormally folded and resistant to proteolytic degradation, and also inhibits proteasomal functions in infected cells, thereby inducing neuronal death. Recent work indicates that the ubiquitin-proteasome system is involved in quality control of PrPC. To reveal the significance of prion protein ubiqitination, we focused on ubiquitin-specific protease 14 (USP14), a deubiqutinating enzyme that catalyzes trimming of polyubiquitin chains and plays a role in regulation of proteasomal processes. Results from the present study showed that treatment with a selective inhibitor of USP14 reduced PrPC, as well as PrPSc, levels in prion-infected neuronal cells. Overexpression of the dominant negative mutant form of USP14 reduced PrPSc, whereas wildtype USP14 increased PrPSc in prion-infected cells. These results suggest that USP14 prevents degradation of both normal and abnormal PrP. Collectively, a better understanding about the regulation of PrPSc clearance caused by USP14 might contribute greatly to the development of therapeutic strategies for prion diseases.
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DOI：
10.1523/jneurosci.2635-09.2009
发表时间：
2009-09-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chen PC;Qin LN;Li XM;Walters BJ;Wilson JA;Mei L;Wilson SM
通讯作者：
Wilson SM
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.6
作者：
Homma T;Ishibashi D;Nakagaki T;Fuse T;Sano K;Satoh K;Atarashi R;Nishida N
通讯作者：
Nishida N
影响因子：
4.8
作者：
Fioriti, L;Dossena, S;Chiesa, R
通讯作者：
Chiesa, R
DOI：
10.1074/mcp.r110.003871
发表时间：
2011-05-01
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Lee, Min Jae;Lee, Byung-Hoon;Finley, Daniel
通讯作者：
Finley, Daniel