King Chih-Yen
Institute of Molecular Biology, Academia Sinica, Taipei, 11529, Taiwan.
Curr Genet. 2025 Mar 29;71(1):8. doi: 10.1007/s00294-025-01313-0.
It was reported that yeast proteins Ssz1 and Upf1 can cure certain [PSI] variants in wild-type cells and there is a special class of variants whose propagation requires the triple mutation of ssz1∆ upf1∆ Hsp104. Attempts to isolate variants with the exact properties from the 74-D694 strain (and tested there) are not yet successful. The effort nevertheless leads to an alternative analysis about how ssz1∆ and upf1∆ mutations can help prion propagation. The cellular propagation of the yeast prion [PSI] requires appropriate activities of the Hsp104 disaggregase. Many [PSI] variants isolated in wild-type strains cannot propagate in cells expressing Hsp104, which has weaker activities. Yet another group of [PSI] variants shows the opposite, propagating well with Hsp104 but is eliminated by the wild-type protein. Deletion of SSZ1 and UPF1 genes in Hsp104 cells generates a just-right environment that supports the propagation of both types of [PSI] variants. The pro-prion effect is not due to the removal of active curing by Ssz1 or Upf1-such curing activity is not observed for the variants. Rather, the double deletion causes a cellular response, which enables more efficient fragmentation of prion fibers, thus remedying the weak activity of Hsp104. The "Goldilocks" conditioning seems also applicable to other yeast prions. Two [PIN] variants that propagate well with wild-type Hsp104 but poorly with Hsp104, lacking residues (2-147), can however thrive with the latter if Ssz1 and Upf1 are also deleted from the cell. In this case, the double deletion results in higher Hsp104 expression, leading to improved generation of prion seeds for robust propagation.
据报道，酵母蛋白Ssz1和Upf1可以治愈野生型细胞中的某些[PSI]变体，并且存在一类特殊的变体，其传播需要ssz1∆ upf1∆ Hsp104的三重突变。从74-D694菌株中分离出具有确切特性的变体（并在那里进行测试）的尝试尚未成功。然而，这项工作导致了对ssz1∆和upf1∆突变如何帮助朊病毒传播的另一种分析。酵母朊病毒[PSI]的细胞传播需要Hsp104解聚酶的适当活性。在野生型菌株中分离出的许多[PSI]变体不能在表达活性较弱的Hsp104的细胞中传播。然而，另一组[PSI]变体则相反，它们在Hsp104存在的情况下传播良好，但会被野生型蛋白消除。在Hsp104细胞中删除SSZ1和UPF1基因会产生一个恰到好处的环境，支持这两种类型的[PSI]变体的传播。前体朊病毒效应不是由于去除了Ssz1或Upf1的活性治愈作用——这些变体没有观察到这种治愈活性。相反，双缺失会引起细胞反应，这使得朊病毒纤维更有效地断裂，从而弥补了Hsp104的弱活性。这种“刚刚好”的调节似乎也适用于其他酵母朊病毒。两种与野生型Hsp104传播良好但与缺少残基（2-147）的Hsp104传播不佳的[PIN]变体，如果细胞中也删除了Ssz1和Upf1，则可以在后者中茁壮成长。在这种情况下，双缺失导致更高的Hsp104表达，从而改善了用于强劲传播的朊病毒种子的产生。
