Codon-specific ribosome stalling reshapes translational dynamics during branched-chain amino acid starvation

IF 10.1 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Lina Worpenberg, Cédric Gobet, Felix Naef
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Abstract

Cells regulate protein synthesis in response to fluctuating nutrient availability through mechanisms that affect both translation initiation and elongation. Branched-chain amino acids, leucine, isoleucine, and valine, are essential nutrients. However, how their depletion affects translation remains largely unclear. Here, we investigate the immediate effects of single, double, and triple branched-chain amino acid deprivation on translational dynamics in NIH3T3 cells using RNA-seq and ribosome profiling. All starvation conditions increased ribosome dwell times, with pronounced stalling at all valine codons during valine and triple starvation, whereas leucine and isoleucine starvation produced milder, codon-specific effects. Notably, stalling under isoleucine deprivation largely decreased under triple starvation. Positional enrichment of valine codons near the 5′ end and downstream isoleucine codons potentially contributes to these patterns, suggesting a possible elongation bottleneck that influences translational responses under branched-chain amino acid starvation. The presence of multiple valine stalling sites was associated with decreased protein levels. Finally, codon-specific dwell time changes correlated strongly with patterns of tRNA isoacceptor charging. Together, these findings suggest that differential ribosome stalling under branched-chain amino acid starvation reflects a balance between amino acid supply, tRNA charging dynamics, codon position, and stress-response signaling.
密码子特异性核糖体失速重塑了支链氨基酸饥饿期间的翻译动力学
细胞通过影响翻译起始和延伸的机制来调节蛋白质合成以响应波动的营养可用性。支链氨基酸,亮氨酸,异亮氨酸和缬氨酸,是必需的营养素。然而,它们的消耗如何影响翻译在很大程度上仍不清楚。在这里,我们利用RNA-seq和核糖体分析研究了单、双和三支链氨基酸剥夺对NIH3T3细胞翻译动力学的直接影响。所有饥饿条件都增加了核糖体的停留时间,在缬氨酸和三重饥饿期间,所有缬氨酸密码子都明显停滞,而亮氨酸和异亮氨酸饥饿只产生较温和的密码子特异性影响。值得注意的是,异亮氨酸剥夺下的失速在三重饥饿下大大减少。靠近5 '端的缬氨酸密码子和下游的异亮氨酸密码子的位置富集可能有助于这些模式,表明可能存在延伸瓶颈,影响支链氨基酸饥饿下的翻译反应。多个瓣膜失速位点的存在与蛋白质水平下降有关。最后,密码子特异性停留时间的变化与tRNA等受体的充电模式密切相关。总之,这些发现表明,支链氨基酸饥饿下的差异核糖体停滞反映了氨基酸供应、tRNA充电动力学、密码子位置和应激反应信号之间的平衡。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Genome Biology
Genome Biology Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
21.00
自引率
3.30%
发文量
241
审稿时长
2 months
期刊介绍: Genome Biology stands as a premier platform for exceptional research across all domains of biology and biomedicine, explored through a genomic and post-genomic lens. With an impressive impact factor of 12.3 (2022),* the journal secures its position as the 3rd-ranked research journal in the Genetics and Heredity category and the 2nd-ranked research journal in the Biotechnology and Applied Microbiology category by Thomson Reuters. Notably, Genome Biology holds the distinction of being the highest-ranked open-access journal in this category. Our dedicated team of highly trained in-house Editors collaborates closely with our esteemed Editorial Board of international experts, ensuring the journal remains on the forefront of scientific advances and community standards. Regular engagement with researchers at conferences and institute visits underscores our commitment to staying abreast of the latest developments in the field.
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