Members of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) protein family catalyze DNA cytosine deamination and underpin a variety of immune defenses. For instance, several family members, including APOBEC3B (A3B), elicit strong retrotransposon and retrovirus restriction activities. However, unlike the other proteins, A3B is the only family member with steady-state nuclear localization. Here, we show that A3B nuclear import is an active process requiring at least one amino acid (Val54) within an N-terminal motif analogous to the nuclear localization determinant of the antibody gene diversification enzyme AID (activation-induced cytosine deaminase). Mechanistic conservation with AID is further suggested by A3B's capacity to interact with the same subset of importin proteins. Despite these mechanistic similarities, enforced A3B expression cannot substitute for AID-dependent antibody gene diversification by class switch recombination. Regulatory differences between A3B and AID are also visible during cell cycle progression. Our studies suggest that the present-day A3B enzyme retained the nuclear import mechanism of an ancestral AID protein during the expansion of the APOBEC3 locus in primates. Our studies also highlight the likelihood that, after nuclear import, specialized mechanisms exist to guide these enzymes to their respective physiological substrates and prevent gratuitous chromosomal DNA damage.
Bibliographical noteFunding Information:
We thank J. Di Noia, M. Herzberg, J. Mueller, and M. Stevenson for reagents; R. LaRue for the phylogenetic schematic; and J. Lee for technical assistance. This work was supported by National Institutes of Health (NIH) Grants R01 AI064046 and P01 GM091743 . L. Lackey was supported in part by a National Science Foundation Pre-doctoral Fellowship and subsequently by a position on the Institute for Molecular Virology Training Grant NIH T32 AI083196 . Z.L. Demorest was supported in part by NIH Grant T32 AI007313 . A.M. Land was supported by a Canadian Institutes of Health Research Postdoctoral Fellowship . J.F. Hultquist was supported by a National Science Foundation Predoctoral Fellowship .
- DNA cytosine deamination
- active nuclear import
- antibody diversification
- retroelement restriction
- subcellular localization