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

Research output: Contribution to journalLetter

6 Citations (Scopus)

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

Fingerprint

Viral Genome
Viruses
Cytosine Deaminase
Herpesviridae
RNA Editing
Ribonucleotide Reductases
Human Herpesvirus 8
Infectious Mononucleosis
Deamination
Single-Stranded DNA
Apolipoproteins B
Retroviridae
Enzymes
DNA Replication
Immunoprecipitation
Innate Immunity
Mutagenesis
Proteomics
Antiviral Agents
HIV-1

PubMed: MeSH publication types

  • 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., ... 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

Epstein–Barr virus BORF2 inhibits cellular APOBEC3B to preserve viral genome integrity. / Cheng, Adam Z.; Yockteng-Melgar, Jaime; Jarvis, Matthew C.; Malik-Soni, Natasha; Borozan, Ivan; Carpenter, Michael A.; McCann, Jennifer L.; Ebrahimi, Diako; Shaban, Nadine M; Marcon, Edyta; Greenblatt, Jack; Brown, William L; Frappier, Lori; Harris, Reuben.

In: Nature Microbiology, Vol. 4, No. 1, 01.01.2019, p. 78-88.

Research output: Contribution to journalLetter

Cheng, AZ, Yockteng-Melgar, J, Jarvis, MC, Malik-Soni, N, Borozan, I, Carpenter, MA, McCann, JL, Ebrahimi, D, Shaban, NM, Marcon, E, Greenblatt, J, Brown, WL, Frappier, L & Harris, R 2019, 'Epstein–Barr virus BORF2 inhibits cellular APOBEC3B to preserve viral genome integrity', Nature Microbiology, vol. 4, no. 1, pp. 78-88. https://doi.org/10.1038/s41564-018-0284-6
Cheng AZ, Yockteng-Melgar J, Jarvis MC, Malik-Soni N, Borozan I, Carpenter MA et al. Epstein–Barr virus BORF2 inhibits cellular APOBEC3B to preserve viral genome integrity. Nature Microbiology. 2019 Jan 1;4(1):78-88. https://doi.org/10.1038/s41564-018-0284-6
Cheng, Adam Z. ; Yockteng-Melgar, Jaime ; Jarvis, Matthew C. ; Malik-Soni, Natasha ; Borozan, Ivan ; Carpenter, Michael A. ; McCann, Jennifer L. ; Ebrahimi, Diako ; Shaban, Nadine M ; Marcon, Edyta ; Greenblatt, Jack ; Brown, William L ; Frappier, Lori ; Harris, Reuben. / Epstein–Barr virus BORF2 inhibits cellular APOBEC3B to preserve viral genome integrity. In: Nature Microbiology. 2019 ; Vol. 4, No. 1. pp. 78-88.
@article{0ae542dc42424331b4c5da9ade2e8eba,
title = "Epstein–Barr virus BORF2 inhibits cellular APOBEC3B to preserve viral genome integrity",
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.",
author = "Cheng, {Adam Z.} and Jaime Yockteng-Melgar and Jarvis, {Matthew C.} and Natasha Malik-Soni and Ivan Borozan and Carpenter, {Michael A.} and McCann, {Jennifer L.} and Diako Ebrahimi and Shaban, {Nadine M} and Edyta Marcon and Jack Greenblatt and Brown, {William L} and Lori Frappier and Reuben Harris",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41564-018-0284-6",
language = "English (US)",
volume = "4",
pages = "78--88",
journal = "Nature Microbiology",
issn = "2058-5276",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Epstein–Barr virus BORF2 inhibits cellular APOBEC3B to preserve viral genome integrity

AU - Cheng, Adam Z.

AU - Yockteng-Melgar, Jaime

AU - Jarvis, Matthew C.

AU - Malik-Soni, Natasha

AU - Borozan, Ivan

AU - Carpenter, Michael A.

AU - McCann, Jennifer L.

AU - Ebrahimi, Diako

AU - Shaban, Nadine M

AU - Marcon, Edyta

AU - Greenblatt, Jack

AU - Brown, William L

AU - Frappier, Lori

AU - Harris, Reuben

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85056656809&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056656809&partnerID=8YFLogxK

U2 - 10.1038/s41564-018-0284-6

DO - 10.1038/s41564-018-0284-6

M3 - Letter

VL - 4

SP - 78

EP - 88

JO - Nature Microbiology

JF - Nature Microbiology

SN - 2058-5276

IS - 1

ER -