Dysregulation of innate interferon signaling by Epstein-Barr virus tegument protein BGLF2

Abstract

Epstein-Barr virus (EBV) successfully infects more than 90% of adults, causing lymphoid or epithelial malignancies such as lymphomas, nasopharyngeal and gastric carcinomas only in a small subset of infected people. EBV can switch between latency and lytic replication in B lymphocytes and epithelial cells. To maintain its life cycle, EBV has to develop mechanisms to evade host innate immune responses. In this study we identified EBV tegument protein BGLF2 as another viral modulator of JAK-STAT-dependent innate immune responses. BGLF2 interacted with STAT2 and promoted its degradation by enhancing K48-linked ubiquitination. BGLF2 also inhibited phosphorylation of JAK1 and STAT1, probably by recruiting a tyrosine phosphatase to these targets. As a result, BGLF2 suppressed ISRE-dependent transcription of interferon (IFN)-stimulated genes (ISGs) induced by type I IFNs. In addition, BGLF2 also exerted an inhibitory effect on type II and type III IFN signaling. Pre-treatment of host cells with IFN-β desensitized them for EBV primary infection and reactivation. Expression of BGLF2 in IFN-β-pre-treated cells reversed IFN-β-mediated inhibition and restored EBV infectivity. Thus, BGLF2 might subserve an IFN-antagonizing function in EBV lytic infection. Our findings reveal a novel EBV modulator of innate IFN response. Supported by HMRF 17160822, RGC C7027-16G and AoE/M-06/08.