Juszkiewicz Szymon, Hegde Ramanujan S
MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
Mol Cell. 2017 Feb 16;65(4):743-750.e4. doi: 10.1016/j.molcel.2016.11.039. Epub 2017 Jan 5.
Diverse cellular stressors have been observed to trigger site-specific ubiquitination on several ribosomal proteins. However, the ubiquitin ligases, biochemical consequences, and physiologic pathways linked to these modifications are not known. Here, we show in mammalian cells that the ubiquitin ligase ZNF598 is required for ribosomes to terminally stall during translation of poly(A) sequences. ZNF598-mediated stalling initiated the ribosome-associated quality control (RQC) pathway for degradation of nascent truncated proteins. Biochemical ubiquitination reactions identified two sites of mono-ubiquitination on the 40S protein eS10 as the primary ribosomal target of ZNF598. Cells lacking ZNF598 activity or containing ubiquitination-resistant eS10 ribosomes failed to stall efficiently on poly(A) sequences. In the absence of stalling, read-through of poly(A) produces a poly-lysine tag, which might alter the localization and solubility of the associated protein. Thus, ribosome ubiquitination can modulate translation elongation and impacts co-translational quality control to minimize production of aberrant proteins.
已观察到多种细胞应激源会触发几种核糖体蛋白上的位点特异性泛素化。然而，与这些修饰相关的泛素连接酶、生化后果和生理途径尚不清楚。在此，我们在哺乳动物细胞中表明，泛素连接酶ZNF598是核糖体在多聚腺苷酸（poly(A)）序列翻译过程中发生终末停滞所必需的。ZNF598介导的停滞启动了核糖体相关质量控制（RQC）途径，以降解新生的截短蛋白。生化泛素化反应确定40S蛋白eS10上的两个单泛素化位点是ZNF598的主要核糖体靶点。缺乏ZNF598活性或含有抗泛素化eS10核糖体的细胞在多聚腺苷酸（poly(A)）序列上不能有效地停滞。在没有停滞的情况下，多聚腺苷酸（poly(A)）的通读会产生一个聚赖氨酸标签，这可能会改变相关蛋白的定位和溶解性。因此，核糖体泛素化可以调节翻译延伸，并影响共翻译质量控制，以尽量减少异常蛋白的产生。
