Abstract
The Epstein-Barr virus (EBV) human herpesvirus is associated with B-cell and epithelial-cell malignancies, and both the latent and lytic forms of viral infection contribute to the development of EBV-associated tumors. Here we show that the Hippo signaling effectors, YAP and TAZ, promote lytic EBV reactivation in epithelial cells. The transcriptional co-activators YAP/TAZ (which are inhibited by Hippo signaling) interact with DNA-binding proteins, particularly TEADs, to induce transcription. We demonstrate that depletion of either YAP or TAZ inhibits the ability of phorbol ester (TPA) treatment, cellular differentiation or the EBV BRLF1 immediate-early (IE) protein to induce lytic EBV reactivation in oral keratinocytes, and show that over-expression of constitutively active forms of YAP and TAZ reactivate lytic EBV infection in conjunction with TEAD family members. Mechanistically, we find that YAP and TAZ interact with, and activate, the EBV BZLF1 immediate-early promoter. Furthermore, we demonstrate that YAP, TAZ, and TEAD family members are expressed at much higher levels in epithelial cell lines in comparison to B-cell lines, and find that EBV infection of oral keratinocytes increases the level of activated (dephosphorylated) YAP and TAZ. Finally, we have discovered that lysophosphatidic acid (LPA), a known YAP/TAZ activator that plays an important role in inflammation, induces EBV lytic reactivation in epithelial cells through a YAP/TAZ dependent mechanism. Together these results establish that YAP/TAZ are powerful inducers of the lytic form of EBV infection and suggest that the ability of EBV to enter latency in B cells at least partially reflects the extremely low levels of YAP/TAZ and TEADs in this cell type.
Highlights
Epstein-Barr virus (EBV) is a gamma herpesvirus that causes the clinical syndrome, infectious mononucleosis, and infects over 90% of the human population
Since we previously showed that AGS gastric carcinoma cells stably infected with the Akata EBV strain (AGS-Akata cells) have an unusually high level of lytic infection [62], and gastric carcinomas often express constitutively active Yes-associated protein (YAP) [63,64], we asked whether YAP expression is required for constitutive lytic EBV protein expression in these cells
Transfected myc-tagged TEAD1 protein preferentially associated with the EBV Zp sequence in ChIP assays (Fig 8C). These results suggest that YAP/TAZ are complexed to TEAD motifs in the YAP-responsive region of the EBV BZLF1 IE promoter in vivo and that direct TEAD binding to Zp is at least partially responsible for its ability to reactivate lytic EBV infection
Summary
Epstein-Barr virus (EBV) is a gamma herpesvirus that causes the clinical syndrome, infectious mononucleosis, and infects over 90% of the human population. EBV primarily infects B cells and oropharyngeal epithelial cells. EBV can infect host cells in either latent or lytic forms. EBV expresses relatively few genes, and the latency proteins produced enable the viral genome to persist and the infected cell to survive. EBV persists in the memory B-cell population in a tightly latent form for the life of the host, but can periodically reactivate to the lytic form of viral infection when B cells are stimulated by antigen and/or differentiate into plasma cells. EBV-infected epithelial cells in the oropharynx generally undergo lytic replication and shed virus into the saliva [7,8,9]
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