Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0830.
Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0830
Proc Natl Acad Sci U S A. 2017 May 23;114(21):E4193-E4202. doi: 10.1073/pnas.1704016114. Epub 2017 May 8.
Overproduction or deficiency of many chaperones and other cellular components cure the yeast prions [] (formed by Sup35p) or [] (based on Ure2p). However, at normal expression levels, Btn2p and Cur1p eliminate most newly arising [] variants but do not cure [], even after overexpression. Deficiency or overproduction of Hsp104 cures the [] prion. Hsp104 deficiency curing is a result of failure to cleave the Sup35p amyloid filaments to make new seeds, whereas Hsp104 overproduction curing occurs by a different mechanism. Hsp104(T160M) can propagate [], but cannot cure it by overproduction, thus separating filament cleavage from curing activities. Here we show that most [] variants arising spontaneously in an strain are cured by restoration of just normal levels of the WT Hsp104. Both strong and weak [] variants are among those cured by this process. This normal-level Hsp104 curing is promoted by Sti1p, Hsp90, and Sis1p, proteins previously implicated in the Hsp104 overproduction curing of []. The [] prion arises in cells at more than 10-fold the frequency in WT cells. The curing activity of Hsp104 thus constitutes an antiprion system, culling many variants of the [] prion at normal Hsp104 levels.
过表达或缺乏许多伴侣蛋白和其他细胞成分可治愈酵母朊病毒 [](由 Sup35p 形成)或[] (基于 Ure2p)。然而，在正常表达水平下，Btn2p 和 Cur1p 消除了大多数新出现的[]变体，但不能治愈[]，即使过表达也是如此。Hsp104 的缺乏或过表达可治愈[]朊病毒。Hsp104 缺乏的治愈是由于无法切割 Sup35p 淀粉样纤维以产生新的种子，而 Hsp104 过表达的治愈则是通过不同的机制发生的。Hsp104(T160M)可以传播[]，但不能通过过表达来治愈它，从而将纤维切割与治愈活动分开。在这里，我们表明，在一个 WT 菌株中自发产生的大多数[]变体通过恢复正常水平的 WT Hsp104 即可被治愈。在这个过程中，强和弱的[]变体都被治愈了。这种正常水平的 Hsp104 治愈受到 Sti1p、Hsp90 和 Sis1p 的促进，这些蛋白先前与 Hsp104 过表达治愈有关。[]朊病毒在 WT 细胞中的出现频率是 WT 细胞的 10 倍以上。因此，Hsp104 的治愈活性构成了一种抗朊病毒系统，在正常的 Hsp104 水平下，可以清除许多[]朊病毒的变体。
