Institut de Recherche en Infectiologie de Montpellier (IRIM), University of Montpellier, CNRS UMR 9004, 1919 route de Mende, 34293 Montpellier, France.
Institut de Génomique Fonctionnelle (IGF), INSERM U1191, 141 Rue de la Cardonille, 34000 Montpellier, France.
Int J Mol Sci. 2024 Oct 29;25(21):11614. doi: 10.3390/ijms252111614.
Codon bias analysis of SARS-CoV-2 reveals suboptimal adaptation for translation in human cells it infects. The detailed examination of the codons preferentially used by SARS-CoV-2 shows a strong preference for Lys, Gln, Glu, and Arg, which are infrequently used in human genes. In the absence of an adapted tRNA pool, efficient decoding of these codons requires a 5-methoxycarbonylmethyl-2-thiouridine (mcms) modification at the U wobble position of the corresponding tRNAs (tLys; tGln; tGlu; tArg). The optimal translation of SARS-CoV-2 open reading frames (ORFs) may therefore require several adjustments to the host's translation machinery, enabling the highly biased viral genome to achieve a more favorable "Ready-to-Translate" state in human cells. Experimental approaches based on LC-MS/MS quantification of tRNA modifications and on alteration of enzymatic tRNA modification pathways provide strong evidence to support the hypothesis that SARS-CoV-2 induces U tRNA modifications and relies on these modifications for its lifecycle. The conclusions emphasize the need for future studies on the evolution of SARS-CoV-2 codon bias and its ability to alter the host tRNA pool through the manipulation of RNA modifications.
SARS-CoV-2 的密码子偏好性分析表明，其在感染的人类细胞中的翻译适应性不佳。对 SARS-CoV-2 偏好使用的密码子的详细检查表明，其强烈偏爱 Lys、Gln、Glu 和 Arg，而这些密码子在人类基因中很少使用。在没有适应的 tRNA 池的情况下，这些密码子的有效解码需要相应 tRNA（tLys；tGln；tGlu；tArg）的 U 摆动位置上的 5-甲氧基羰基甲基-2-硫尿苷（mcms）修饰。因此，SARS-CoV-2 开放阅读框（ORF）的最佳翻译可能需要对宿主的翻译机制进行几种调整，以使高度偏向性的病毒基因组在人类细胞中达到更有利的“准备翻译”状态。基于 LC-MS/MS 定量 tRNA 修饰和改变酶 tRNA 修饰途径的实验方法提供了强有力的证据支持 SARS-CoV-2 诱导 U tRNA 修饰并依赖这些修饰来完成其生命周期的假说。这些结论强调了未来研究 SARS-CoV-2 密码子偏好性的进化及其通过操纵 RNA 修饰改变宿主 tRNA 池的能力的必要性。
