A BRRF1-CCR4-NOT axis underlies conserved transcriptome-wide loss of splicing fidelity during gammaherpesvirus reactivation
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.
Show abstract
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 Kaposis 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.
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