Kaposi’s sarcoma-associated herpesvirus induces specialised ribosomes to efficiently translate viral lytic mRNAs

James C. Murphy, Elena M. Harrington, Sophie Schumann, Elton J. R. Vasconcelos, Timothy J. Mottram, Katherine L. Harper, Julie L. Aspden and Adrian Whitehouse ()
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James C. Murphy: University of Leeds
Elena M. Harrington: University of Leeds
Sophie Schumann: University of Leeds
Elton J. R. Vasconcelos: LeedsOmics, University of Leeds
Timothy J. Mottram: University of Leeds
Katherine L. Harper: University of Leeds
Julie L. Aspden: University of Leeds
Adrian Whitehouse: University of Leeds

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-35914-5

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