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

Abstract

Historically, ribosomes have been viewed as unchanged homogeneous macromolecular machines with no intrinsic regulatory capacity for mRNA translation. However, an emerging concept is that heterogeneity of ribosomal composition exists, which can exert 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 a high translational demand on the host cell during replication. Here we explore the possibility that Kaposi sarcoma associated herpesvirus can manipulate host ribosome biogenesis during infection to produce specialised ribosomes which preferentially translate viral transcripts. Quantitative proteomic analysis has identified changes in the stoichiometry and composition of precursor ribosomal complexes during the switch from latent to lytic KSHV replication. Intriguingly, we demonstrate the enhanced association of ribosomal biogenesis factors BUD23 and NOC4L, and a previously uncharacterised KSHV lytic protein, ORF11, with small ribosomal subunit precursor complexes during lytic KSHV infection. Notably, BUD23 depletion resulted in significantly reduced viral gene expression and progression through the lytic cascade, culminating in a dramatic reduction of infectious virion production. Importantly, ribosome profiling demonstrated that BUD23 is essential for the reduced association of ribosomes with KSHV uORFs in late lytic genes, required for the efficient translation of the main open reading frame. Together our results provide new mechanistic insights into KSHV-mediated manipulation of cellular ribosome composition inducing a population of specialised ribosomes to facilitate efficient translation of viral mRNAs.

Ribosomal control in RNA virus-infected cells

“…This discovery suggests a promising future for the development of drugs targeting heterogeneous ribosomes. The heterogeneity of ribosomal components in Kaposi’s sarcoma-associated herpesvirus infected cells has been analyzed using quantitative proteomics ( Murphy et al, 2022 ). The deletion of ribosomal biogenesis factor BUD23 was found to significantly inhibit the replication of viral particles ( Murphy et al, 2022 ).…”

“…The heterogeneity of ribosomal components in Kaposi’s sarcoma-associated herpesvirus infected cells has been analyzed using quantitative proteomics ( Murphy et al, 2022 ). The deletion of ribosomal biogenesis factor BUD23 was found to significantly inhibit the replication of viral particles ( Murphy et al, 2022 ). This suggests that the inhibition of new heterogeneous ribosome production after viral infection of host cells can effectively kill viral particles in the organism.…”