Epstein-Barr virus nuclear antigen EBNA3A modulates IRF3-dependent IFNβ expression

Journal of Biological Chemistry, vol. 300, pp. 107645

Abstract

Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis, persistently infects over 90% of the human adult population and is associated with several human cancers. To establish life-long infection, EBV tampers with the induction of type I interferon (IFN I)-dependent antiviral immunity in the host. How various EBV genes help orchestrate this crucial strategy is incompletely defined. Here, we reveal a mechanism by which the EBV nuclear antigen 3A (EBNA3A) may inhibit IFNβ induction. Using proximity biotinylation we identify the histone acetyltransferase P300, a member of the IFNβ transcriptional complex, as a binding partner of EBNA3A. We further show that EBNA3A also interacts with the activated IFN-inducing transcription factor interferon regulatory factor 3 that collaborates with P300 in the nucleus. Both events are mediated by the N-terminal domain of EBNA3A. We propose that EBNA3A limits the binding of interferon regulatory factor 3 to the IFNβ promoter, thereby hampering downstream IFN I signaling. Collectively, our findings suggest a new mechanism of immune evasion by EBV, affected by its latency gene EBNA3A.

Authors 9

1. Sanne L. Landman Aachen

   Leiden University Medical Center · Oncode Institute

   Affiliation as printed

   Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center (LUMC), Leiden, the Netherlands

2. Maaike E. Ressing Aachen Department of Cell and Chemical Biology

   Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, the Netherlands

3. Anna M. Gram Aachen Department of Cell and Chemical Biology

   Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, the Netherlands

4. Rayman T.N. Tjokrodirijo Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics & Metabolomics, LUMC, Leiden, the Netherlands

5. Peter A. van Veelen Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics & Metabolomics, LUMC, Leiden, the Netherlands

6. Jacques Neefjes Aachen

   Leiden University Medical Center · Oncode Institute

   Affiliation as printed

   Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center (LUMC), Leiden, the Netherlands

7. Rob C. Hoeben Aachen Department of Cell and Chemical Biology

   Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, the Netherlands

8. Annemarthe G. van der Veen Aachen Department of Immunology, LUMC

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology, LUMC, Leiden, the Netherlands

9. Ilana Berlin corresponding Aachen

   Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center (LUMC), Leiden, the Netherlands. Electronic address: i.berlin@lumc.nl