Epstein–Barr virus BORF2 inhibits cellular APOBEC3B to preserve viral genome integrity

Adam Z. Cheng, Jaime Yockteng-Melgar, Matthew C. Jarvis, Natasha Malik-Soni, Ivan Borozan, Michael A. Carpenter, Jennifer L. McCann, Diako Ebrahimi, Nadine M Shaban, Edyta Marcon, Jack Greenblatt, William L Brown, Lori Frappier, Reuben Harris

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Abstract

The apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like (APOBEC) family of single-stranded DNA (ssDNA) cytosine deaminases provides innate immunity against virus and transposon replication1–4. A well-studied mechanism is APOBEC3G restriction of human immunodeficiency virus type 1, which is counteracted by a virus-encoded degradation mechanism1–4. Accordingly, most work has focused on retroviruses with obligate ssDNA replication intermediates and it is unclear whether large double-stranded DNA (dsDNA) viruses may be similarly susceptible to restriction. Here, we show that the large dsDNA herpesvirus Epstein–Barr virus (EBV), which is the causative agent of infectious mononucleosis and multiple cancers5, utilizes a two-pronged approach to counteract restriction by APOBEC3B. Proteomics studies and immunoprecipitation experiments showed that the ribonucleotide reductase large subunit of EBV, BORF26,7, binds APOBEC3B. Mutagenesis mapped the interaction to the APOBEC3B catalytic domain, and biochemical studies demonstrated that BORF2 stoichiometrically inhibits APOBEC3B DNA cytosine deaminase activity. BORF2 also caused a dramatic relocalization of nuclear APOBEC3B to perinuclear bodies. On lytic reactivation, BORF2-null viruses were susceptible to APOBEC3B-mediated deamination as evidenced by lower viral titres, lower infectivity and hypermutation. The Kaposi’s sarcoma-associated herpesvirus homologue, ORF61, also bound APOBEC3B and mediated relocalization. These data support a model where the genomic integrity of human γ-herpesviruses is maintained by active neutralization of the antiviral enzyme APOBEC3B.

Original languageEnglish (US)
Pages (from-to)78-88
Number of pages11
JournalNature Microbiology
Volume4
Issue number1
DOIs
StatePublished - Jan 1 2019

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  • Letter
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

Cite this

Cheng, A. Z., Yockteng-Melgar, J., Jarvis, M. C., Malik-Soni, N., Borozan, I., Carpenter, M. A., McCann, J. L., Ebrahimi, D., Shaban, N. M., Marcon, E., Greenblatt, J., Brown, W. L., Frappier, L., & Harris, R. (2019). Epstein–Barr virus BORF2 inhibits cellular APOBEC3B to preserve viral genome integrity. Nature Microbiology, 4(1), 78-88. https://doi.org/10.1038/s41564-018-0284-6