The Role of Amino-Terminal Sequences in Cellular Localization and Antiviral Activity of APOBEC3B
- 1 September 2011
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 85 (17), 8538-8547
- https://doi.org/10.1128/jvi.02645-10
Abstract
Human APOBEC3B (A3B) has been described as a potent inhibitor of retroviral infection and retrotransposition. However, we found that the predominantly nuclear A3B only weakly restricted infection by HIV-1, HIV-1Δ vif , and human T-cell leukemia virus type 1 (HTLV-1), while significantly inhibiting LINE-1 retrotransposition. The chimeric construct A3G/B, in which the first 60 amino acids of A3B were replaced with those of A3G, restricted HIV-1, HIV-1Δ vif , and HTLV-1 infection, as well as LINE-1 retrotransposition. In contrast to the exclusively cytoplasmic A3G, which is inactive against LINE-1 retrotransposition, the A3G/B protein, while localized mainly to the cytoplasm, was also present in the nucleus. Further mutational analysis revealed that residues 18, 19, 22, and 24 in A3B were the major determinants for nuclear versus cytoplasmic localization and antiretroviral activity. HIV-1Δ vif packages A3G, A3B, and A3G/B into particles with close-to-equal efficiencies. Mutation E68Q or E255Q in the active centers of A3G/B resulted in loss of the inhibitory activity against HIV-1Δ vif , while not affecting activity against LINE-1 retrotransposition. The low inhibition of HIV-1Δ vif by A3B correlated with a low rate of G-to-A hypermutation. In contrast, viruses that had been exposed to A3G/B showed a high number of G-to-A transitions. The mutation pattern was similar to that previously reported for A3B, with a preference for the GA context. In summary, these observations suggest that changing 4 residues in the amino terminus of A3B not only retargets the protein from the nucleus to the cytoplasm but also enhances its ability to restrict HIV while retaining inhibition of retrotransposition.Keywords
This publication has 47 references indexed in Scilit:
- Quantitative profiling of the full APOBEC3 mRNA repertoire in lymphocytes and tissues: implications for HIV-1 restrictionNucleic Acids Research, 2010
- Interactions of host APOBEC3 restriction factors with HIV-1 in vivo: implications for therapeuticsExpert Reviews in Molecular Medicine, 2010
- Multiple ways of targeting APOBEC3–virion infectivity factor interactions for anti-HIV-1 drug developmentTrends in Pharmacological Sciences, 2009
- HIV-1 Vif-mediated ubiquitination/degradation of APOBEC3G involves four critical lysine residues in its C-terminal domainProceedings of the National Academy of Sciences of the United States of America, 2009
- APOBEC3BDeletion and Risk of HIV‐1 AcquisitionThe Journal of Infectious Diseases, 2009
- The intrinsic antiretroviral factor APOBEC3B contains two enzymatically active cytidine deaminase domainsVirology, 2007
- DNA Deamination in Immunity: AID in the Context of Its APOBEC RelativesAdvances in Immunology, 2007
- Resistance of human T cell leukemia virus type 1 to APOBEC3G restriction is mediated by elements in nucleocapsidProceedings of the National Academy of Sciences of the United States of America, 2007
- Cellular inhibitors of long interspersed element 1 and Alu retrotranspositionProceedings of the National Academy of Sciences of the United States of America, 2006
- Cytidine Deamination of Retroviral DNA by Diverse APOBEC ProteinsCurrent Biology, 2004