ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Quality Control Function by Mediating Regulatory 40S Ribosomal Ubiquitylation.
ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Quality Control Function by Mediating Regulatory 40S Ribosomal Ubiquitylation.
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DOI：
10.1016/j.molcel.2016.12.026
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发表时间：
2017-02-16
期刊：
影响因子：
16
通讯作者：
Bennett EJ
中科院分区：
文献类型：
--
作者：
Sundaramoorthy E;Leonard M;Mak R;Liao J;Fulzele A;Bennett EJ
在翻译过程中经历末端停滞的核糖体可以通过核糖体相关的质量控制(QC)途径来解决，QC途径监督mRNA和新生链的破坏并回收核糖体亚基。识别停滞的核糖体和启动哺乳动物核糖体相关QC事件的近端因子仍未确定。我们证明ZNF598泛素连接酶和40S核糖体蛋白RACK1有助于解决Poly(A)诱导的停滞的核糖体。他们通过调控不同的和重叠的40S核糖体泛素化事件来实现这一点。ZNF598主要调节RPS10和RPS20的泛素化，而RACK1调节RPS2、RPS3和RPS20的泛素化。ZNF598功能的获得或丧失或阻止RPS10或RPS20泛素化的突变会导致停滞的核糖体的错误分辨和随后含有PolyA的停滞序列的读取。综上所述，我们的结果表明，ZNF598、RACK1和40S调节泛素化在哺乳动物核糖体相关的QC通路中发挥着关键作用。
Ribosomes that experience terminal stalls during translation are resolved by ribosome-associated quality control (QC) pathways that oversee mRNA and nascent chain destruction and recycle ribosomal subunits. The proximal factors that sense stalled ribosomes and initiate mammalian ribosome-associated QC events remain undefined. We demonstrate that the ZNF598 ubiquitin ligase and the 40S ribosomal protein RACK1 help to resolve poly(A)-induced stalled ribosomes. They accomplish this by regulating distinct and overlapping regulatory 40S ribosomal ubiquitylation events. ZNF598 primarily mediates regulatory ubiquitylation of RPS10 and RPS20, whereas RACK1 regulates RPS2, RPS3, and RPS20 ubiquitylation. Gain or loss of ZNF598 function or mutations that block RPS10 or RPS20 ubiquitylation result in defective resolution of stalled ribosomes and subsequent readthrough of poly(A)-containing stall sequences. Together, our results indicate that ZNF598, RACK1, and 40S regulatory ubiquitylation plays a pivotal role in mammalian ribosome-associated QC pathways.