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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DOI：
10.1038/s41467-023-35914-5
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发表时间：
2023-01-18
影响因子：
16.6
通讯作者：
Whitehouse, Adrian
中科院分区：
文献类型：
--
作者：
Murphy, James C.;Harrington, Elena M.;Schumann, Sophie;Vasconcelos, Elton J. R.;Mottram, Timothy J.;Harper, Katherine L.;Aspden, Julie L.;Whitehouse, Adrian
历史上，核糖体被视为未改变的均质大分子机器，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，在翻译控制中发挥调节功能或特异性。最近的发现证实了这一点，该发现确定了成分不同的专门核糖体，这些核糖体可以主动调节 mRNA 翻译。病毒缺乏自己的翻译机制，在复制过程中对宿主提出很高的翻译要求。我们探索了 KSHV 操纵核糖体生物发生产生专门的核糖体的可能性，这些核糖体优先翻译病毒转录本。定量蛋白质组学分析确定了从潜伏复制转变为裂解复制期间前体核糖体复合物的化学计量和组成的变化。我们证明了核糖体生物发生因子 BUD23 和 NOC4L 以及 KSHV ORF11 蛋白与裂解复制过程中小核糖体亚基前体复合物的关联增强。 BUD23 耗竭导致病毒基因表达显着减少，最终导致感染性病毒颗粒产生的急剧减少。核糖体分析表明，BUD23 对于减少核糖体与晚期裂解基因中 KSHV uORF 的关联至关重要，这是下游编码序列有效翻译所必需的。结果提供了对 KSHV 介导的细胞核糖体组成操纵的机制见解，该操纵诱导一群专门的核糖体促进病毒 mRNA 的有效翻译。病毒依靠宿主细胞的翻译机制来合成病毒蛋白。我们表明，KSHV 操纵宿主细胞核糖体的组成，创建专门的核糖体来特异性翻译病毒 mRNA。
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. Viruses rely on the translational machinery of the host cell to synthesis viral proteins. We show that KSHV manipulates the composition of host cell ribosomes creating a specialised ribosome to specifically translate viral mRNAs.
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影响因子：
3.8
作者：
Calderwood, MA;Hall, KT;Whitehouse, A
通讯作者：
Whitehouse, A
影响因子：
7.7
作者：
Harper, Katherine L.;Mottram, Timothy J.;Anene, Chinedu A.;Foster, Becky;Patterson, Molly R.;McDonnell, Euan;Macdonald, Andrew;Westhead, David;Whitehouse, Adrian
通讯作者：
Whitehouse, Adrian
影响因子：
9.8
作者：
Armistead, Joy;Khatkar, Sunita;Triggs-Raine, Barbara
通讯作者：
Triggs-Raine, Barbara
影响因子：
14.9
作者：
Brinkman EK;Chen T;Amendola M;van Steensel B
通讯作者：
van Steensel B
影响因子：
5.3
作者：
Figaro, Sabine;Wacheul, Ludivine;Heurgue-Hamard, Valerie
通讯作者：
Heurgue-Hamard, Valerie