Evidence linking APOBEC3B genesis and evolution of innate immune antagonism by gamma-herpesvirus ribonucleotide reductases
- University of Minnesota, United States
- 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
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.
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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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
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