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

Michiel Van Gent,Adrian Reich,Sadanandan E Velu,Michaela U Gack,Bill Sugden

doi:10.1371/journal.pbio.3001097

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.

Highlights

Herpesviruses are large, enveloped DNA viruses that establish widespread persistent infections
We started by determining the effect of small interfering polyadenylated nuclear RNA (RNA)-mediated depletion of the critical nonsense-mediated decay (NMD) component UPF1 on spontaneous Epstein–Barr virus (EBV) reactivation in the human gastric carcinoma cell line AGS-EBV, which harbors recombinant EBV Akata-BX1 that encodes green fluorescent protein (GFP) under control of the lytic BXLF1 promoter [32]
Fluorescence microscopy and flow cytometry analyses of AGS-EBV cells showed that UPF1 silencing markedly increased the proportion of cells expressing GFP, a measure of EBV reactivation, to a similar extent as treatment with sodium butyrate (NaB), a known potent inducer of EBV reactivation that served as a positive control (Fig 1A and 1B)

Summary

Introduction

Herpesviruses are large, enveloped DNA viruses that establish widespread persistent infections. The 2 human oncogenic gammaherpesviruses Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) are carried by a large proportion of the adult population worldwide and pose a significant risk of infection-associated morbidity and mortality, especially in immunocompromised hosts [1,2,3]. Both EBV and KSHV cause a range of malignancies of lymphoid, epithelial, and endothelial origin, and KSHV remains one of the leading causes of death in HIV patients [2,4,5]. While major improvements have been made in our understanding of the viral factors involved

Methods

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Conclusion