Sundaramoorthy Elayanambi, Leonard Marilyn, Mak Raymond, Liao Jeffrey, Fulzele Amitkumar, Bennett Eric J
Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Mol Cell. 2017 Feb 16;65(4):751-760.e4. doi: 10.1016/j.molcel.2016.12.026. Epub 2017 Jan 26.
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.
在翻译过程中经历终末停滞的核糖体，可通过核糖体相关质量控制（QC）途径来解决，该途径负责监督信使核糖核酸（mRNA）和新生链的降解，并使核糖体亚基循环利用。感知停滞核糖体并启动哺乳动物核糖体相关QC事件的近端因子仍未明确。我们证明，锌指蛋白598（ZNF598）泛素连接酶和40S核糖体蛋白活化蛋白C激酶1（RACK1）有助于解决多聚腺苷酸（poly(A)）诱导的停滞核糖体问题。它们通过调节不同且重叠的40S核糖体泛素化事件来实现这一点。ZNF598主要介导核糖体蛋白S10（RPS10）和核糖体蛋白S20（RPS20）的调节性泛素化，而RACK1则调节RPS2、RPS3和RPS20的泛素化。ZNF598功能的获得或丧失，或阻断RPS10或RPS20泛素化的突变，都会导致停滞核糖体的解决出现缺陷，并随后通读含poly(A)的停滞序列。总之，我们的结果表明，ZNF598、RACK1和40S调节性泛素化在哺乳动物核糖体相关QC途径中起关键作用。
