Kaposi’s sarcoma-associated herpesvirus induces specialized 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 ‘specialized ribosomes’ that actively regulate mRNA translation. Viruses lack their own translational machinery and impose a high translational demand on the host cell during replication. Whilst viruses have evolved a variety of mechanisms to overcome this, we hypothesize that some viruses manipulate the host cell to produce specialized ribosomes to 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 uncharacterized 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 insight into KSHV-mediated manipulation of cellular ribosome composition inducing a population of specialized ribosomes to facilitate efficient translation of viral mRNAs.

ORGANISM(S): Human gammaherpesvirus 8 Homo sapiens

PROVIDER: GSE199095 | GEO | 2022/12/14

REPOSITORIES: GEO