PolyQ‐expanded huntingtin and ataxin‐3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin
PolyQ‐expanded huntingtin and ataxin‐3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin
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DOI：
10.1096/fj.201700801rr
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发表时间：
2018-01
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影响因子：
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通讯作者：
Hui Yang;H. Yue;Wen-tian He;Jun-Ye Hong;Leilei Jiang;Hong-Yu Hu
中科院分区：
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作者：
Hui Yang;H. Yue;Wen-tian He;Jun-Ye Hong;Leilei Jiang;Hong-Yu Hu
泛素（Ub）-蛋白酶体系统的组分，如Ub、Ub衔接子或蛋白酶体亚基，通常与聚集的蛋白质一起聚集在包涵体中，但蛋白质聚集体如何隔离Ub相关蛋白仍然是一个谜。使用N-末端亨廷顿蛋白（Htt-N552）和共济失调蛋白（Atx）-3作为模型蛋白，我们研究了PolyQ-扩增蛋白隔离Ub衔接子的分子机制。我们发现polyQ-扩增的Htt-N552和Atx-3将内源性UB衔接子、人RAD 23同源物B（hHR 23 B）和泛素（UBQLN）-2隔离到包涵体中。这种螯合作用依赖于Ub衔接子的乌巴结构域和聚集蛋白的缀合的Ub。此外，polyQ-扩展的Htt-N552和Atx-3通过封存hHR 23 B来降低C组着色性干皮病（XPC）的蛋白水平，表明该过程可能会减少hHR 23 B的可用量，从而影响其稳定XPC的正常功能。我们的研究结果表明，polyQ扩增蛋白通过致病蛋白的泛素化将Ub衔接子或其他Ub相关蛋白隔离成聚集体或包涵体。这项研究也可能为细胞中Ub阳性包涵体的形成提供一种共同的机制。杨，H.，H.-W·岳他W-T洪，J-Y Jiang，L. -L. Hu，H. -Y PolyQ-扩增的亨廷顿蛋白和共济失调蛋白-3通过缀合的泛素将泛素衔接子hHR 23 B和UBQLN 2螯合成聚集体。FASEB J. 32，2923 - 2933（2018）。www.fasebj.org
The components of ubiquitin (Ub)‐proteasome system, such as Ub, Ub adaptors, or proteasome subunits, are commonly accumulated with the aggregated proteins in inclusions, but how protein aggregates sequester Ub‐related proteins remains elusive. Using N‐terminal huntingtin (Htt‐N552) and ataxin (Atx)‐3 as model proteins, we investigated the molecular mechanism underlying sequestration of Ub adaptors by polyQ‐expanded proteins. We found that polyQ‐expanded Htt‐N552 and Atx‐3 sequester endogenous Ub adaptors, human RAD23 homolog B (hHR23B) and ubiquilin (UBQLN)‐2, into inclusions. This sequestration effect is dependent on the UBA domains of Ub adaptors and the conjugated Ub of the aggregated proteins. Moreover, polyQ‐expanded Htt‐N552 and Atx‐3 reduce the protein level of xeroderma pigmentosum group C (XPC) by sequestration of hHR23B, suggesting that this process may cut down the available quantity of hHR23B and thus affect its normal function in stabilizing XPC. Our findings demonstrate that polyQ‐expanded proteins sequester Ub adaptors or other Ub‐related proteins into aggregates or inclusions through ubiquitination of the pathogenic proteins. This study may also provide a common mechanism for the formation of Ub‐positive inclusions in cells.—Yang, H., Yue, H.‐W., He, W.‐T., Hong, J.‐Y., Jiang, L.‐L., Hu, H.‐Y. PolyQ‐expanded huntingtin and ataxin‐3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin. FASEB J. 32, 2923–2933 (2018). www.fasebj.org