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VIRAL INNATE IMMUNITY

APOBEC restriction goes nuclear

Nature Microbiology volume 4, pages 6–7 (2019)Cite this article

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APOBEC3 restriction, known to inhibit retroviruses by interfering with genome replication and hypermutating viral DNA, targets the γ-herpesvirus Epstein–Barr virus and is antagonized by the viral BORF2 protein.

Epstein–Barr virus (EBV) is a large, double-stranded DNA virus that infects B lymphocytes, causes mononucleosis (glandular fever) and is associated with multiple malignancies, including Burkitt’s lymphoma and nasopharyngeal carcinoma. In proteomic-based screens for cellular proteins that interact with EBV proteins, published in this issue of Nature Microbiology, Cheng and colleagues3 have made the unanticipated discovery that the large subunit of viral ribonucleotide reductase (called BORF2) engages one particular APOBEC3 protein, APOBEC3B, a nuclear family member that is associated with the induction of somatic mutations in a variety of human cancers4. Enzymatic assays using purified proteins demonstrated that BORF2 directly inhibits APOBEC3B-mediated editing of a single-stranded DNA template. Importantly, an elegant series of virological assays, in which APOBEC3B and/or BORF2 were present or absent during lytic EBV replication, revealed that APOBEC3B increases viral mutational burden at predicted deamination target sequences, and that BORF2 prevents this. Consistent with increased mutagenesis being detrimental, BORF2-deficient virus is ~twofold less infectious, but only in the presence of APOBEC3B (an effect that would be amplified during spreading infections). It will now be of interest to ascertain the significance of the APOBEC3B–BORF2 interaction for EBV-induced mononucleosis and cancers — studying humans with over-expressed or variant APOBEC3B alleles should be informative in this regard5,6.

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Fig. 1: Mechanisms of viral evasion from APOBEC3-mediated restriction.

References

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  1. Department of Infectious Diseases, School of Immunology and Microbial Sciences, King’s College London, London, UK

    Michael H. Malim & Darja Pollpeter

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  1. Michael H. Malim
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  2. Darja Pollpeter
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Correspondence to Michael H. Malim or Darja Pollpeter.

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Malim, M.H., Pollpeter, D. APOBEC restriction goes nuclear. Nat Microbiol 4, 6–7 (2019). https://doi.org/10.1038/s41564-018-0323-3

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