Huntingtin Polyglutamine Fragments Are a Substrate for Hsp104 in Saccharomyces cerevisiae.
Huntingtin Polyglutamine Fragments Are a Substrate for Hsp104 in Saccharomyces cerevisiae.
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亨廷顿聚谷氨酰胺片段是酿酒酵母中 Hsp104 的底物。
DOI：
10.1128/mcb.00122-21
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发表时间：
2021
影响因子：
5.3
通讯作者：
Greene,LoisE
中科院分区：
文献类型：
--
作者：
Wayne,NicoleJ;Dembny,KatherineE;Pease,Tyler;Saba,Farrin;Zhao,Xiaohong;Masison,DanielC;Greene,LoisE
亨廷顿氏病的起因是亨廷顿蛋白片段聚集在聚谷氨酰胺重复区（HttpolyQ）上，这取决于酵母中淀粉样蛋白构象的朊病毒的存在。由于这种关系，HttpolyQ聚集间接依赖于Hsp104，因为Hsp104在朊病毒传播中起着至关重要的作用。我们发现，无论是否存在[RNQ+]和[PSI+]朊病毒，Hsp104都会直接影响HttQ103的聚集。当我们在朊病毒存在下灭活Hsp104时，酵母细胞只有一个或几个大的HttQ103聚集体，而不是许多小的聚集体。当我们在没有朊病毒的情况下灭活Hsp104时，HttQ103没有明显的聚集，而在激活Hsp104时，由于Hsp104切断了自发成核的聚集体，HttQ103聚集体积累缓慢。由于在聚谷氨酰胺区下游有一个富含脯氨酸的区域，我们没有观察到这两种效应，因为HttQ103P不能自发成核，而Hsp104不能有效地切断朊病毒成核的HttQ103P聚集体。因此，Hsp104在HttQ103P聚集中的唯一作用是繁殖酵母朊病毒。综上所述，由于Hsp104有效地切断了HttQ103的聚合，而不是HttQ103P的聚合，所以它对HttQ103的聚合有明显的影响，而对HttQ103P的聚合没有影响。
The aggregation of huntingtin fragments with expanded polyglutamine repeat regions (HttpolyQ) that cause Huntington’s disease depends on the presence of a prion with an amyloid conformation in yeast. As a result of this relationship, HttpolyQ aggregation indirectly depends on Hsp104 due to its essential role in prion propagation. We find that HttQ103 aggregation is directly affected by Hsp104 with and without the presence of [RNQ+] and [PSI+] prions. When we inactivate Hsp104 in the presence of prion, yeast cells have only one or a few large HttQ103 aggregates rather than numerous smaller aggregates. When we inactivate Hsp104 in the absence of prion, there is no significant aggregation of HttQ103, whereas with active Hsp104, HttQ103 aggregates accumulate slowly due to the severing of spontaneously nucleated aggregates by Hsp104. We do not observe either effect with HttQ103P, which has a polyproline-rich region downstream of the polyglutamine region, because HttQ103P does not spontaneously nucleate and Hsp104 does not efficiently sever the prion-nucleated HttQ103P aggregates. Therefore, the only role of Hsp104 in HttQ103P aggregation is to propagate yeast prion. In conclusion, because Hsp104 efficiently severs the HttQ103 aggregates but not HttQ103P aggregates, it has a marked effect on the aggregation of HttQ103 but not HttQ103P.