Nonsense-mediated decay controls the reactivation of the oncogenic herpesviruses EBV and KSHV

Abstract

The oncogenic human herpesviruses Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) are the causative agents of multiple malignancies. A hallmark of herpesviruses is their biphasic life cycle consisting of latent and lytic infection. In this study, we identified that cellular nonsense-mediated decay (NMD), an evolutionarily conserved RNA degradation pathway, critically regulates the latent-to-lytic switch of EBV and KSHV infection. The NMD machinery suppresses EBV and KSHV Rta transactivator expression and promotes maintenance of viral latency by targeting the viral polycistronic transactivator transcripts for degradation through the recognition of features in their 3′ UTRs. Treatment with a small-molecule NMD inhibitor potently induced reactivation in a variety of EBV- and KSHV-infected cell types. In conclusion, our results identify NMD as an important host process that controls oncogenic herpesvirus reactivation, which may be targeted for the therapeutic induction of lytic reactivation and the eradication of tumor cells.

Rta is the principal activator of Epstein-Barr virus epithelial lytic transcription

“…Gammaherpesviruses have evolved multiple mechanisms to repress expression of their ORF50 homologs, achieving exquisite control of entry into the lytic cycle. Recent work has shown that ORF50 transcripts, by including splice junctions downstream of the ORF50 stop codon are degraded by nonsense mediated decay that must be subverted to achieve lytic cycle entry [ 45 , 46 ]. In the case of EBV, further repression is achieved by extensive methylation of the Rta promoter in B lymphocytes, the site of latency, that requires binding of Zta to methylated response elements to overcome [ 10 , 11 , 13 , 15 , 16 , 29 ].…”

“…Since our ChIP assays suggested that Rta/Zta synergy was not operating at the level of promoter binding, we considered the possibility that Zta was increasing the stability of Rta induced transcripts. Indeed, recent reports have shown that modulation of mRNA stability is a key mechanism by which gammaherpesvirus regulate the transition from latent infection to lytic replication [45][46][47]. Hypothesizing that Zta might interfere with the nonsense mediated decay (NMD) pathway to stabilize lytic transcripts, we tested whether NMD inhibition could substitute for Zta expression in increasing the levels of Rta synergy transcripts.…”

Caspases Switch off the m 6 A RNA Modification Pathway to Foster the Replication of a Ubiquitous Human Tumor Virus

“…Emerging studies suggested that mRNA decay pathways play an important role in restricting gamma-herpesvirus reactivation. Proteins involved in nonsense-mediated mRNA decay have been shown by the Gack and Karijolich labs to restrict EBV and KSHV replication ( 54 , 55 ). Our current discovery of multiple proteins within the m 6 A RNA modification pathway as EBV restriction factors further enhances our understanding of the control of herpesvirus reactivation at the RNA level.…”

ΔNp63α promotes Epstein-Barr virus latency in undifferentiated epithelial cells

“…Interestingly, p38 kinase was also recently reported to inhibit nonsense mediated decay (NMD) of RNA in cells with DNA damage [ 107 ]. Since NMD was recently shown to promote degradation of the transcript encoding the BZLF1 and BRLF1 genes in latently infected cells [ 108 ], decreasing NMD of this transcript in the context of the intact viral genome could be another post-transcriptional mechanism by which p38 kinase promotes lytic EBV reactivation.…”