Human Retroviral Host Restriction Factors APOBEC3G and APOBEC3F Localize to mRNA Processing Bodies

Abstract

APOBEC3G is an antiviral host factor capable of inhibiting the replication of both exogenous and endogenous retroviruses as well as hepatitis B, a DNA virus that replicates through an RNA intermediate. To gain insight into the mechanism whereby APOBEC3G restricts retroviral replication, we investigated the subcellular localization of the protein. Herein, we report that APOBEC3G localizes to mRNA processing (P) bodies, cytoplasmic compartments involved in the degradation and storage of nontranslating mRNAs. Biochemical analysis revealed that APOBEC3G localizes to a ribonucleoprotein complex with other P-body proteins which have established roles in cap-dependent translation (eIF4E and eIF4E-T), translation suppression (RCK/p54), RNA interference–mediated post-transcriptional gene silencing (AGO2), and decapping of mRNA (DCP2). Similar analysis with other APOBEC3 family members revealed a potential link between the localization of APOBEC3G and APOBEC3F to a common ribonucleoprotein complex and P-bodies with potent anti–HIV-1 activity. In addition, we present evidence suggesting that an important role for HIV-1 Vif, which subverts both APOBEC3G and APOBEC3F antiviral function by inducing their degradation, could be to selectively remove these proteins from and/or restrict their localization to P-bodies. Taken together, the results of this study reveal a novel link between innate immunity against retroviruses and P-bodies suggesting that APOBEC3G and APOBEC3F could function in the context of P-bodies to restrict HIV-1 replication. Successful replication of viruses and other intracellular pathogens in their respective host cells requires that they overcome a series of replication restrictions or “roadblocks” established by the cell. In the case of HIV-1, the ability of the virus to replicate in human cells is dependent on its ability to neutralize APOBEC3G, a DNA editing enzyme that incorporates into virions and renders them noninfectious. Although a potentially devastating inhibitor of HIV-1 replication, the virus evades APOBEC3G by inducing its degradation during virus assembly. APOBEC3G is also capable of inhibiting the replication of other retroviruses as well as the hepadnavirus hepatitis B, a DNA virus that replicates through an RNA intermediate, suggesting that APOBEC3G may function in cellular defense against a broad range of viral pathogens. Here, Rana and colleagues present their findings that APOBEC3G localizes to specialized compartments in the cytoplasm of mammalian cells known as mRNA processing (P) bodies, which function in the degradation and storage of cellular mRNA. Furthermore, they show that APOBEC3G assembles into a ribonucleoprotein complex with P-body proteins involved in translation, translation suppression, RNA interference, and mRNA decapping. These novel and exciting findings have broad-scale implications for APOBEC3G function and for the role of P-bodies in both cellular defense against viruses and retroviral assembly.