Antiviral Function of APOBEC3G Can Be Dissociated from Cytidine Deaminase Activity

• Published in: Current biology Vol. 15; no. 2; pp. 166 - 170
• Main Authors: Newman, Edmund N.C., Holmes, Rebecca K., Craig, Heather M., Klein, Kevin C., Lingappa, Jaisri R., Malim, Michael H., Sheehy, Ann M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 26.01.2005
• Subjects: Amino Acid Motifs; Antiviral Agents - physiology; APOBEC-3G Deaminase; Cells, Cultured; Cytidine Deaminase - metabolism; Enzyme-Linked Immunosorbent Assay; Gene Products, vif - metabolism; HIV-1; Humans; Mutagenesis, Site-Directed; Mutation - genetics; Mutation - physiology; Nucleoside Deaminases; Protein Structure, Tertiary; Proteins - physiology; Repressor Proteins; vif Gene Products, Human Immunodeficiency Virus; Virion - metabolism
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2004.12.068

The antiretroviral activity of the cellular enzyme APOBEC3G [1] has been attributed to the excessive deamination of cytidine (C) to uridine (U) in minus strand reverse transcripts, a process resulting in guanosine (G) to adenosine (A) hypermutation of plus strand DNAs [2–5]. The HIV-1 Vif protein counteracts APOBEC3G by inducing proteasomal degradation and exclusion from virions through recruitment of a cullin5 ECS E3 ubiquitin ligase complex [6–13]. APOBEC3G belongs to the APOBEC protein family, members of which possess consensus (H/C)-(A/V)-E-(X)24-30-P-C-(X)2-C cytidine deaminase motifs [14]. Earlier analyses of APOBEC-1 have defined specific residues that are important for zinc coordination, proton transfer, and, therefore, catalysis within this motif [15]. Because APOBEC3G contains two such motifs, we used site-directed mutagenesis of conserved residues to assess each region's contribution to anti-HIV-1 activity. Surprisingly, whereas either the N- or C-terminal domain could confer antiviral function in tissue culture-based infectivity assays, only an intact C-terminal motif was essential for DNA mutator activity. These findings reveal the nonequivalency of APOBEC3G's N- and C-terminal domains and imply that APOBEC3G-mediated DNA editing may not always be necessary for antiviral activity. Accordingly, we propose that APOBEC3G can achieve an anti-HIV-1 effect through an undescribed mechanism that is distinct from cytidine deamination.