Inhibition of a Yeast LTR Retrotransposon by Human APOBEC3 Cytidine Deaminases

Abstract

The mammalian APOBEC3 family of cytidine deaminases includes several members that possess potent antiretroviral activity. Human APOBEC3F and APOBEC3G are specifically incorporated into human immunodeficiency virus type 1 (HIV-1) progeny virions in the absence of virion infectivity factor (Vif), where they deaminate deoxycytidine to deoxyuridine on the minus strand of nascent reverse transcripts. Editing of the HIV-1 cDNA leads to its degradation or to G to A hypermutation of the integrated provirus. Here, we show that APOBEC3 proteins also restrict the activity of a distantly related long terminal repeat (LTR) retrotransposon. When expressed in the yeast Saccharomyces cerevisiae, human APOBEC3C, APOBEC3F, or APOBEC3G or mouse APOBEC3 potently inhibit replication of the Ty1 LTR retrotransposon. APOBEC3G interacts with Ty1 Gag and is packaged into Ty1 virus-like particles (VLPs) by a mechanism that closely resembles the one it uses to enter HIV-1 virions. Expression of APOBEC3G results in a reduced level of Ty1 cDNA integration and G to A editing of integrated Ty1 cDNA. Our findings indicate that APOBEC3G restricts Ty1 and HIV-1 by similar mechanisms and suggest that the APOBEC3 proteins target a substantially broader spectrum of retroelements than previously appreciated.

Large-scale DNA editing of retrotransposons accelerates mammalian genome evolution

“…Investigation of the sequences surrounding the edited nucleotides revealed dominance of adenosines at position + 2 relative to the editing site (GxA→AxA motif; the underlined G is the editing site; Methods and Supplementary Table S1). This is in agreement with previous experimental studies [14][15][16][17][18][19][20]23,24 and supports the identification of these mismatches as an outcome of mouse APOBEC3 activity.…”

“…This process is thus called DNA editing. In recent years, it was shown that active LTR (long terminal repeat) retrotransposons, which are endogenous retroviruses, can also be edited [14][15][16][17][18][19][20][21] . However, the impact of DNA editing on genome variability has not been explored to date 22 .…”

Interferon‐inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication†

“…8,9 The cytidine deaminase APOBEC3G (A3G), which is encoded within a cluster of seven related editing enzymes (APOBEC3A-G) on chromosome 22, provides broad innate immunity against exogenous and endogenous retroelements. [10][11][12][13][14][15][16] Encapsidated into the retroviral particle A3G deaminates dCs of the retroviral minus strand cDNA immediately on reverse transcription within the infected cell, and the formation of dUs leads to premature degradation of the retroviral cDNA or to non-functional hypermutated proviruses. [10][11][12][13][14][15][16] HIV overcomes this innate defense barrier in T-cells with the help of the HIV-encoded Vif (virion infectivity factor) protein that specifically targets A3G to proteosomal degradation.…”

“…[10][11][12][13][14][15][16] Encapsidated into the retroviral particle A3G deaminates dCs of the retroviral minus strand cDNA immediately on reverse transcription within the infected cell, and the formation of dUs leads to premature degradation of the retroviral cDNA or to non-functional hypermutated proviruses. [10][11][12][13][14][15][16] HIV overcomes this innate defense barrier in T-cells with the help of the HIV-encoded Vif (virion infectivity factor) protein that specifically targets A3G to proteosomal degradation. [17][18][19] In addition, the editing enzymes APOBEC3F (A3F) and APOBEC3B (A3B) inhibit HIV-1, and A3B and APOBEC3C (A3C) restrict simian immunodeficiency virus replication by cytidine deamination of the viral minus strand cDNA, and A3B and to a lesser extent also A3F are resistant to HIV Vif-induced proteosomal degradation.…”

APOBEC3F and APOBEC3G mRNA Levels Do Not Correlate with Human Immunodeficiency Virus Type 1 Plasma Viremia or CD4 + T-Cell Count

“…hA3G has received considerable attention as an innate mechanism of cellular defense against retroviral infection and as a potential target for antiretroviral therapy. While it is clear that hA3G can counteract multiple retroviruses as well as retrotransposons in vitro (6,7,15,22), its usefulness as a clinical marker of infection remains unclear. Further studies to elucidate the clinical utility of hA3G and hA3F may include the examination of CD4 ϩ T cells rather than PBMCs and follow a larger cohort over time to examine the predictive relationship on progression to AIDS.…”