Optimization of Codon Translation Rates via tRNA Modifications Maintains Proteome Integrity.
Optimization of Codon Translation Rates via tRNA Modifications Maintains Proteome Integrity.
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DOI：
10.1016/j.cell.2015.05.022
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发表时间：
2015-06-18
期刊：
影响因子：
64.5
通讯作者：
Leidel SA
中科院分区：
文献类型：
--
作者：
Nedialkova DD;Leidel SA
蛋白质开始折叠，因为它们从核糖体翻译出来。核糖体转运沿着给定mRNA的动力学可以影响新生链折叠，但是单个密码子翻译速率影响蛋白质组完整性的程度仍然未知。在这里，我们表明，较慢的解码离散密码子eltered广泛的蛋白质聚集在体内。使用核糖体分析，我们发现在一个tRNA子集中失去反密码子摆动尿苷（U34）修饰导致核糖体在酿酒酵母和秀丽隐杆线虫中的同源密码子处暂停。缺乏U34修饰的细胞表现出蛋白毒性应激的基因表达标志，积累内源性蛋白质的聚集体，并且在清除应激诱导的蛋白质聚集体方面严重受损。低修饰的tRNA的过度表达会导致核糖体暂停，同时恢复蛋白质稳态。我们的研究结果表明，修改U34是一个进化保守的加速器解码，并揭示了一个意想不到的作用tRNA修饰在维持蛋白质组的完整性。tRNA反密码子修饰的缺失减缓了体内同源密码子的翻译。密码子特异性翻译暂停触发酵母和蠕虫中的蛋白质错误折叠。密码子翻译速率和蛋白质稳态通过tRNA过表达得以恢复。最佳密码子翻译速率--由tRNA反密码子中核苷修饰的存在所确保--对于维持蛋白质组的完整性至关重要。
Proteins begin to fold as they emerge from translating ribosomes. The kinetics of ribosome transit along a given mRNA can influence nascent chain folding, but the extent to which individual codon translation rates impact proteome integrity remains unknown. Here, we show that slower decoding of discrete codons elicits widespread protein aggregation in vivo. Using ribosome profiling, we find that loss of anticodon wobble uridine (U34) modifications in a subset of tRNAs leads to ribosome pausing at their cognate codons in S. cerevisiae and C. elegans. Cells lacking U34 modifications exhibit gene expression hallmarks of proteotoxic stress, accumulate aggregates of endogenous proteins, and are severely compromised in clearing stress-induced protein aggregates. Overexpression of hypomodified tRNAs alleviates ribosome pausing, concomitantly restoring protein homeostasis. Our findings demonstrate that modified U34 is an evolutionarily conserved accelerator of decoding and reveal an unanticipated role for tRNA modifications in maintaining proteome integrity. tRNA anticodon modification loss slows translation at cognate codons in vivo Codon-specific translational pausing triggers protein misfolding in yeast and worms Codon translation rates and protein homeostasis are restored by tRNA overexpression Optimal codon translation rates—ensured by the presence of nucleoside modifications in the tRNA anticodon—are critical for maintaining proteome integrity.