Gammaherpesvirus reactivation drives a collapse of host mRNA splicing fidelity that extends across the transcriptome, with exon skipping affecting up to ~57% of expressed genes, exceeding the effects of depletion of any of 186 splicing factors. Combining five Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) reactivation systems across B cell and epithelial models with deep poly(A)+ RNA sequencing of purified lytic cells, we find that most induced isoforms are predicted to undergo nonsense- mediated decay or to lose conserved protein domains, broadly compromising cell cycle, innate immune and RNA-processing pathways. The phenotype arises independently of viral DNA replication, indicating early host remodeling. A screen of EBV early genes identifies BRRF1 as a key driver: through a CIY(Y/E) motif conserved in KSHV ORF49, BRRF1 engages the nuclear CCR4-NOT complex through its CNOT9 and CNOT1 subunits, hijacking this canonically cytoplasmic deadenylation hub for nuclear disruption of host splicing.
Nguyen, T. T., Ghosh, A., O'Grady, T., Roberts, C., Ishaq, E., Wickramarachchige-Dona, N., Bass, J., Lam, M., Baddoo, M., Ungerleider, N., Otterloo, N. V., Zhang, Q., Liu, H., Dong, Y., Renne, R., Nguyen, T. D., Flemington, E.
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