The APOBEC3 family of DNA cytosine deaminases has important roles in innate immunity and cancer. It is unclear how DNA tumor viruses regulate these enzymes and how these interactions, in turn, impact the integrity of both the viral and cellular genomes. Polyomavirus (PyVs) are small DNA pathogens that contain oncogenic potentials. In this study, we examined the effects of PyV infection on APOBEC3 expression and activity. We demonstrate that APOBEC3B is specifically upregulated by BK polyomavirus (BKPyV) infection in primary kidney cells and that the upregulated enzyme is active. We further show that the BKPyV large T antigen, as well as large T antigens from related polyomaviruses, is alone capable of upregulating APOBEC3B expression and activity. Furthermore, we assessed the impact of A3B on productive BKPyV infection and viral genome evolution. Although the specific knockdown of APOBEC3B has little short-term effect on productive BKPyV infection, our informatics analyses indicate that the preferred target sequences of APOBEC3B are depleted in BKPyV genomes and that this motif underrepresentation is enriched on the nontranscribed stand of the viral genome, which is also the lagging strand during viral DNA replication. Our results suggest that PyV infection upregulates APOBEC3B activity to influence virus sequence composition over longer evolutionary periods. These findings also imply that the increased activity of APOBEC3B may contribute to PyV-mediated tumorigenesis.
Bibliographical noteFunding Information:
We thank Richard Frisque for the JCPyV pBS-JCT(Int-) plasmid, Ellen Cahir-McFarland for thoughtful comments, and James DeCaprio for MCPyV reagents. Salary support for G.J.S. was provided by a National Science Foundation Graduate Research Fellowship (grant 00039202). R.S.H. is an Investigator of Howard Hughes Medical Institute. Jiang lab contributions were supported in part by the UAB Department of Microbiology start-up fund, AHA Scientist Development grant 15SDG25680061, and NIH grant R01AI123162. R.S.H. is a cofounder, shareholder, and consultant of ApoGen Biotechnologies Inc. A research project in the Harris laboratory is supported by Biogen.