Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0830, USA.
Genetics. 2011 Jun;188(2):339-48. doi: 10.1534/genetics.111.127779. Epub 2011 Apr 5.
[URE3] is an amyloid-based prion of Ure2p, a regulator of nitrogen catabolism in Saccharomyces cerevisiae. The Ure2p of the human pathogen Candida albicans can also be a prion in S. cerevisiae. We find that overproduction of the disaggregating chaperone, Hsp104, increases the frequency of de novo [URE3] prion formation by the Ure2p of S. cerevisiae and that of C. albicans. This stimulation is strongly dependent on the presence of the [PIN(+)] prion, known from previous work to enhance [URE3] prion generation. Our data suggest that transient Hsp104 overproduction enhances prion generation through persistent effects on Rnq1 amyloid, as well as during overproduction by disassembly of amorphous Ure2 aggregates (generated during Ure2p overproduction), driving the aggregation toward the amyloid pathway. Overproduction of other major cytosolic chaperones of the Hsp70 and Hsp40 families (Ssa1p, Sse1p, and Ydj1p) inhibit prion formation, whereas another yeast Hsp40, Sis1p, modulates the effects of Hsp104p on both prion induction and prion curing in a prion-specific manner. The same factor may both enhance de novo prion generation and destabilize existing prion variants, suggesting that prion variants may be selected by changes in the chaperone network.
[URE3] 是 Ure2p 所形成的淀粉样蛋白样朊病毒，Ure2p 是酿酒酵母氮分解代谢的调控因子。白色念珠菌（一种人类病原体）的 Ure2p 也可以在酿酒酵母中形成朊病毒。我们发现，解聚伴侣蛋白 Hsp104 的过表达会增加酿酒酵母和白色念珠菌的 Ure2p 从头形成 [URE3] 朊病毒的频率。这种刺激强烈依赖于 [PIN(+)] 朊病毒的存在，先前的研究表明，该朊病毒增强了 [URE3] 朊病毒的产生。我们的数据表明，瞬时 Hsp104 过表达通过对 Rnq1 淀粉样蛋白的持续影响，以及通过解聚无定形 Ure2 聚集体（在 Ure2p 过表达期间产生）来增强朊病毒的生成，从而促进聚集向淀粉样蛋白途径。Hsp70 和 Hsp40 家族的其他主要细胞质伴侣蛋白（Ssa1p、Sse1p 和 Ydj1p）的过表达抑制朊病毒的形成，而另一种酵母 Hsp40，Sis1p，以朊病毒特异性的方式调节 Hsp104p 对朊病毒诱导和朊病毒消除的影响。同一个因素可能同时增强新形成的朊病毒的产生并破坏现有的朊病毒变体，这表明朊病毒变体可能是通过伴侣蛋白网络的变化选择的。
