Ribosomal surveillance pathways scan for ribosomes that are transiently paused or terminally stalled owing to structural elements in mRNAs or nascent chain sequences1, 2. Some stalls in budding yeast are sensed by the GTPase Hbs1, which loads Dom34, a catalytically inactive member of the archaeo-eukaryotic release factor 1 superfamily. Hbs1–Dom34 and the ATPase Rli1 dissociate stalled ribosomes into 40S and 60S subunits. However, the 60S subunits retain the peptidyl-tRNA nascent chains, which recruit the ribosome quality control complex that consists of Rqc1–Rqc2–Ltn1–Cdc48–Ufd1–Npl4. Nascent chains ubiquitylated by the E3 ubiquitin ligase Ltn1 are extracted from the 60S subunit by the ATPase Cdc48–Ufd1–Npl4 and presented to the 26S proteasome for degradation3–9. Failure to degrade the nascent chains leads to protein aggregation and proteotoxic stress in yeast and neurodegeneration in mice10–14. Despite intensive investigations on the ribosome quality control pathway, it is not known how the tRNA is hydrolysed from the ubiquitylated nascent chain before its degradation. Here we show that the Cdc48 adaptor Vms1 is a peptidyl-tRNA hydrolase. Similar to classical eukaryotic release factor 1, Vms1 activity is dependent on a conserved catalytic glutamine. Evolutionary analysis indicates that yeast Vms1 is the founding member of a clade of eukaryotic release factor 1 homologues that we designate the Vms1-like release factor 1 clade.The Cdc48 adaptor Vms1 is a peptidyl-tRNA hydrolase that cooperates with the ribosome quality control complex to catalyse the removal of nascent polypeptides from stalled ribosomes.

中文翻译：

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Vms1 和 ANKZF1 肽基-tRNA 水解酶从停滞的核糖体中释放新生链

核糖体监测通路扫描因 mRNA 或新生链序列中的结构元件而暂时暂停或最终停滞的核糖体 1, 2. 萌芽酵母中的一些停滞由 GTPase Hbs1 感知，它加载 Dom34，古细菌的催化失活成员真核释放因子 1 超家族。Hbs1–Dom34 和 ATPase Rli1 将停滞的核糖体分解为 40S 和 60S 亚基。然而，60S 亚基保留了肽基-tRNA 新生链，它招募由 Rqc1–Rqc2–Ltn1–Cdc48–Ufd1–Npl4 组成的核糖体质量控制复合物。由 E3 泛素连接酶 Ltn1 泛素化的新生链由 ATPase Cdc48–Ufd1–Npl4 从 60S 亚基中提取，并呈递给 26S 蛋白酶体进行降解 3–9。未能降解新生链会导致酵母中的蛋白质聚集和蛋白毒性应激以及小鼠的神经变性 10-14。尽管对核糖体质量控制途径进行了深入研究，但尚不清楚 tRNA 在降解前如何从泛素化新生链中水解。在这里，我们展示了 Cdc48 适配器 Vms1 是一种肽基-tRNA 水解酶。类似于经典的真核释放因子 1，Vms1 的活性依赖于保守的催化谷氨酰胺。进化分析表明酵母 Vms1 是真核释放因子 1 同系物进化枝的创始成员，我们将其命名为 Vms1 样释放因子 1 进化枝。 Cdc48 接头 Vms1 是一种肽基-tRNA 水解酶，与核糖体质量控制复合物合作以催化从停滞的核糖体中去除新生多肽。