Gorkovskiy et al. observed that many [PSI⁺] prion isolates, obtained in yeast with the mutant Hsp104^T160M chaperone, propagate poorly in wild‐type cells and suggested that Hsp104 is part of the cellular anti‐prion system, curing many nascent [PSI⁺] variants. Here, we argue that the concept may require reassessment. We induced [PSI⁺] variants in both the wild‐type and the mutant background. Three new variants were isolated in the T160M background. They exhibited lower thermostability, possessed novel structural features, and were inherently mutable, changing to well‐characterized VH, VK, and VL variants in wild‐type cells. In contrast, VH, VK, and VL of the wild‐type background, could not change freely and were lost in the mutant, due to insufficient chaperone activity. Thus, mutant Hsp104 can impose as much restriction against emerging prion variants as the wild‐type protein. Such restriction conserved the transmutable variants in the T160M background, since new structures mis‐templated from them could not gain a foothold. We further demonstrate excess Hsp104^T160M or Hsp104^∆2‐147 can eliminate nearly all of the [PSI⁺] variants in their native background. This finding contradicts the generally held belief that Hsp104‐induced [PSI⁺] curing requires its N‐terminal domain, and may help settling the current contention regarding how excess Hsp104 cures [PSI⁺].

中文翻译：

---

有缺陷的 Hsp104 分子伴侣稳定了可变酵母朊病毒变体

戈尔科夫斯基等人。观察到许多 [ PSI ⁺ ] 朊病毒分离物，在酵母中获得的 Hsp104 ^T160M伴侣蛋白突变体，在野生型细胞中繁殖不佳，并表明 Hsp104 是细胞抗朊病毒系统的一部分，治愈了许多新生的 [ PSI ⁺ ] 变体。在这里，我们认为这个概念可能需要重新评估。我们诱导 [ PSI ⁺] 野生型和突变体背景中的变体。在 T160M 背景中分离出三个新变体。它们表现出较低的热稳定性，具有新的结构特征，并且具有固有的可变性，在野生型细胞中转变为特征明确的 VH、VK 和 VL 变体。相比之下，由于伴侣活性不足，野生型背景的 VH、VK 和 VL 不能自由改变并在突变体中丢失。因此，突变体 Hsp104 可以对新出现的朊病毒变体施加与野生型蛋白质一样多的限制。这种限制保留了 T160M 背景中的可变变体，因为从它们错误模板化的新结构无法立足。我们进一步证明了过量的 Hsp104 ^T160M或 Hsp104 ^∆2-147可以消除其原生背景中几乎所有的 [ PSI ⁺ ] 变体。这一发现与普遍持有的观点相矛盾，即 Hsp104 诱导的 [ PSI ⁺ ] 治愈需要其 N 端结构域，并且可能有助于解决当前关于过量 Hsp104 如何治愈 [ PSI ⁺ ] 的争论。