Kaposi's sarcoma-associated herpesvirus induces specialised ribosomes to efficiently translate viral lytic mRNAs
Kaposi's sarcoma-associated herpesvirus induces specialised ribosomes to efficiently translate viral lytic mRNAs
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卡波西肉瘤相关疱疹病毒诱导特化核糖体有效翻译病毒裂解性 mRNA
DOI：
10.1101/2022.03.11.483946
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Murphy J
中科院分区：
文献类型：
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作者：
Murphy J
从历史上看，核糖体被认为是不变的同质大分子机器，没有mRNA翻译的调节能力。一个新兴的概念是，核糖体组成的异质性存在，发挥调节功能或翻译控制的特异性。这一点得到了最近发现的支持，这些发现鉴定了积极调节mRNA翻译的组成不同的专门核糖体。病毒缺乏自己的翻译机制，在复制过程中对宿主施加高翻译要求。我们探讨的可能性，KSHV操纵核糖体生物合成产生专门的核糖体，优先翻译病毒转录本。定量蛋白质组学分析确定的化学计量和组成的前体核糖体复合物的变化过程中的开关从潜伏到裂解复制。我们证明了核糖体生物合成因子BUD23和NOC4L，以及KSHV ORF 11蛋白，在裂解复制过程中与小核糖体亚基前体复合物的增强关联。BUD23缺失导致病毒基因表达显著降低，最终导致感染性病毒体产生的急剧减少。核糖体分析表明，BUD23对于减少核糖体与晚期裂解基因中的KSHV uORF的缔合是必需的，这是下游编码序列的有效翻译所必需的。结果提供了机制的见解KSHV介导的操纵细胞核糖体组成诱导一群专门的核糖体促进病毒mRNA的有效翻译。
Historically, ribosomes were viewed as unchanged homogeneous macromolecular machines with no regulatory capacity for mRNA translation. An emerging concept is that heterogeneity of ribosomal composition exists, exerting a regulatory function or specificity in translational control. This is supported by recent discoveries identifying compositionally distinct specialised ribosomes that actively regulate mRNA translation. Viruses lack their own translational machinery and impose high translational demands on the host during replication. We explore the possibility that KSHV manipulates ribosome biogenesis producing specialised ribosomes which preferentially translate viral transcripts. Quantitative proteomic analysis identified changes in the stoichiometry and composition of precursor ribosomal complexes during the switch from latent to lytic replication. We demonstrate the enhanced association of ribosomal biogenesis factors BUD23 and NOC4L, and the KSHV ORF11 protein, with small ribosomal subunit precursor complexes during lytic replication. BUD23 depletion resulted in significantly reduced viral gene expression, culminating in dramatic reduction of infectious virion production. Ribosome profiling demonstrated BUD23 is essential for reduced association of ribosomes with KSHV uORFs in late lytic genes, required for the efficient translation of the downstream coding sequence. Results provide mechanistic insights into KSHV-mediated manipulation of cellular ribosome composition inducing a population of specialised ribosomes facilitating efficient translation of viral mRNAs.