Antiviral Function of APOBEC3G Can Be Dissociated From Cytidine Deaminase Activity

Curr Biol. 2005 Jan 26;15(2):166-70. doi: 10.1016/j.cub.2004.12.068.

Abstract

The antiretroviral activity of the cellular enzyme APOBEC3G 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. 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. 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. Earlier analyses of APOBEC-1 have defined specific residues that are important for zinc coordination, proton transfer, and, therefore, catalysis within this motif. 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • APOBEC-3G Deaminase
  • Amino Acid Motifs
  • Antiviral Agents / physiology*
  • 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
  • Virion / metabolism
  • vif Gene Products, Human Immunodeficiency Virus

Substances

  • Antiviral Agents
  • Gene Products, vif
  • Proteins
  • Repressor Proteins
  • vif Gene Products, Human Immunodeficiency Virus
  • Nucleoside Deaminases
  • APOBEC-3G Deaminase
  • APOBEC3G protein, human
  • Cytidine Deaminase