Evidence linking APOBEC3B genesis and evolution of innate immune antagonism by gamma-herpesvirus ribonucleotide reductases

  1. Sofia N Moraes
  2. Jordan T Becker
  3. Seyed Arad Moghadasi
  4. Nadine M Shaban
  5. Ashley A Auerbach
  6. Adam Z Cheng
  7. Reuben S Harris  Is a corresponding author
  1. University of Minnesota, United States
  2. The University of Texas Health Science Center at San Antonio, United States

Abstract

Viruses have evolved diverse mechanisms to antagonize host immunity such as direct inhibition and relocalization of cellular APOBEC3B (A3B) by the ribonucleotide reductase (RNR) of Epstein-Barr virus. Here, we investigate the mechanistic conservation and evolutionary origin of this innate immune counteraction strategy. First, we find that human gamma-herpesvirus RNRs engage A3B via largely distinct surfaces. Second, we show that RNR-mediated enzymatic inhibition and relocalization of A3B depend upon binding to different regions of the catalytic domain. Third, we show that the capability of viral RNRs to antagonize A3B is conserved among gamma-herpesviruses that infect humans and Old World monkeys that encode this enzyme but absent in homologous viruses that infect New World monkeys that naturally lack the A3B gene. Finally, we reconstruct the ancestral primate A3B protein and demonstrate that it is active and similarly engaged by the RNRs from viruses that infect humans and Old World monkeys but not by the RNRs from viruses that infect New World monkeys. These results combine to indicate that the birth of A3B at a critical branchpoint in primate evolution may have been a driving force in selecting for an ancestral gamma-herpesvirus with an expanded RNR functionality through counteraction of this antiviral enzyme.

Data availability

All data generated and analyzed during this study are included in the manuscript and supporting files. Numerical data for the bar plots and ridgeline plots in Figure 2, Figure 3, and Figure 4 are provided in Source data 1. Source Data Files containing uncropped gel images and raw files for immunoblots and deaminase activity assays are provided for Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, Figure 8, Figure 8-figure supplement 2, and Figure 8-figure supplement 3. GenBank codes for the sequences used in this study are listed in the Materials and Methods section.

Article and author information

Author details

  1. Sofia N Moraes

    Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0838-0047
  2. Jordan T Becker

    Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0239-5443
  3. Seyed Arad Moghadasi

    Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Nadine M Shaban

    Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ashley A Auerbach

    Department of Biochemistry and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8505-5905
  6. Adam Z Cheng

    Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Reuben S Harris

    Department of Biochemistry, Molecular Biology, and Biophysics, The University of Texas Health Science Center at San Antonio, San Antonio, United States
    For correspondence
    rsh@uthscsa.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9034-9112

Funding

National Institute of Allergy and Infectious Diseases (R37-AI064046)

  • Reuben S Harris

National Cancer Institute (P01-CA234228)

  • Reuben S Harris

National Institute of Allergy and Infectious Diseases (F31-AI161910)

  • Sofia N Moraes

National Institute of Allergy and Infectious Diseases (F32-AI147813)

  • Jordan T Becker

National Institute of Allergy and Infectious Diseases (R56-AI150402)

  • Nadine M Shaban

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jan E Carette, Stanford University School of Medicine, United States

Version history

  1. Preprint posted: April 4, 2022 (view preprint)
  2. Received: October 4, 2022
  3. Accepted: October 12, 2022
  4. Accepted Manuscript published: December 2, 2022 (version 1)
  5. Version of Record published: December 13, 2022 (version 2)

Copyright

© 2022, Moraes et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sofia N Moraes
  2. Jordan T Becker
  3. Seyed Arad Moghadasi
  4. Nadine M Shaban
  5. Ashley A Auerbach
  6. Adam Z Cheng
  7. Reuben S Harris
(2022)
Evidence linking APOBEC3B genesis and evolution of innate immune antagonism by gamma-herpesvirus ribonucleotide reductases
eLife 11:e83893.
https://doi.org/10.7554/eLife.83893

Share this article

https://doi.org/10.7554/eLife.83893

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