Atypical ubiquitination by E3 ligase WWP1 inhibits the proteasome-mediated degradation of mutant huntingtin
Atypical ubiquitination by E3 ligase WWP1 inhibits the proteasome-mediated degradation of mutant huntingtin
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E3 连接酶 WWP1 的非典型泛素化抑制突变亨廷顿蛋白的蛋白酶体介导的降解
DOI：
10.1016/j.brainres.2016.03.027
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发表时间：
2016-07
期刊：
影响因子：
2.9
通讯作者：
Li He
中科院分区：
文献类型：
--
作者：
Lin Li;Jin Zhenzhen;Tan Huiping;Xu Qiaoqiao;Peng Ting;Li He
亨廷顿病（Huntington's disease，HD）是由亨廷顿蛋白（Huntingtin，Htt）基因第1外显子CAG三核苷酸重复序列扩增引起的疾病，其特征是聚集形成含有扩增的多聚谷氨酰胺（polyQ）重复序列的突变型Htt。泛素-蛋白酶体系统（UPS）的功能障碍在HD的发病机制中起着至关重要的作用。E3泛素连接酶作为泛素与特定靶蛋白之间的连接介质，已被认为参与mHtt降解和HD病理。然而，尚未探索E3连接酶WWP 1在HD中的潜在参与。本研究确定WWP 1是否参与HD在体内和体外模型中的发展。结果显示，与其他几种E3连接酶相比，WWP 1的表达在表达突变型Htt（160 Q）的小鼠和N2 a细胞中增强，并与mHtt蛋白聚集体共定位。此外，WWP 1的表达正调节突变Htt水平、聚集体形成和细胞毒性。进一步的分析表明，WWP 1泛素化的mHtt在一个非典型的位置的赖氨酸-63，这可能有抑制降解的突变体Htt通过泛素-蛋白酶体途径。总之，这些结果表明，E3连接酶WWP 1参与HD的发病机制，因此，它可能是一个新的治疗干预的目标。
Huntington's disease (HD) is caused by the expansion of CAG trinucleotide repeats in exon 1 of HD gene encoding huntingtin (Htt), which is characterized by aggregation and formation of mutant Htt containing expanded polyglutamine (polyQ) repeats. Dysfunction of the ubiquitin-proteasome system (UPS) plays a critical role in the pathogenesis of HD. As the linkage mediator between ubiquitin and specific target proteins, E3 ubiquitin ligases have been suggested to be involved in mHtt degradation and HD pathology. However, the potential involvement of the E3 ligase WWP1 in HD has not been explored. The present study determined whether WWP1 is involved in the development of HD in bothin vivoandin vitromodels. The results showed that in contrast to several other E3 ligases, expression of WWP1 is enhanced in mice and N2a cells expressing mutant Htt (160Q) and co-localized with mHtt protein aggregates. In addition, expression of WWP1 positively regulates mutan Htt levels, aggregate formation, and cell toxicity. Further analysis revealed that WWP1 ubiquitinated mHtt at an atypical position of Lys-63, which may have inhibited degradation of mutant Htt through the ubiquitin-proteasome pathway. In conclusion, these results suggested that the E3 ligase WWP1 is involved in the pathogenesis of HD; therefore, it may be a novel target for therapeutic intervention.
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影响因子：
64.5
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
通讯作者：
Yao, TP
DOI：
10.1074/jbc.m110.187591
发表时间：
2011-07-15
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Zucchelli S;Marcuzzi F;Codrich M;Agostoni E;Vilotti S;Biagioli M;Pinto M;Carnemolla A;Santoro C;Gustincich S;Persichetti F
通讯作者：
Persichetti F
影响因子：
13.3
作者：
Li XJ;Li H;Li S
通讯作者：
Li S
影响因子：
16
作者：
Venkatraman, P;Wetzel, R;Goldberg, AL
通讯作者：
Goldberg, AL
影响因子：
6.1
作者：
Tang, Bin;Seredenina, Tamara;Coppola, Giovanni;Kuhn, Alexandre;Geschwind, Daniel H.;Luthi-Carter, Ruth;Thomas, Elizabeth A.
通讯作者：
Thomas, Elizabeth A.