Transcriptional Regulation of APOBEC3G, a Cytidine Deaminase That Hypermutates Human Immunodeficiency Virus

Kristine M Rose,Mariana Marin,Susan L Kozak,David Kabat

doi:10.1074/jbc.m406760200

Abstract

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) is an antiretroviral deoxycytidine deaminase that lethally hypermutates human immunodeficiency virus type 1 (HIV-1) but is itself neutralized by the HIV-1-encoded viral infectivity factor. Accordingly, APOBEC3G occurs specifically in human T lymphocytic cell lines that contain this antiviral defense, including H9. Since the substrate specificities of related cytidine deaminases are strongly influenced by their intracellular quantities, we analyzed the factors that control APOBEC3G expression. The levels of APOBEC3G mRNA and protein were unaffected by treatment of proliferating H9 cells with interferons or tumor necrosis factor-alpha but were enhanced up to 20-fold by phorbol myristate acetate. This induction was mediated at the transcriptional level by a pathway that required activation of the protein kinase Calpha/betaI isozyme (PKC), mitogen-activated protein kinase kinase (MEK) 1 and 2, and extracellular signal-regulated kinase (ERK). Correspondingly, induction of APOBEC3G was blocked by multiple inhibitors that act at diverse steps of this pathway. The PKCalpha/betaI/MEK/ERK pathway also controlled basal levels of APOBEC3G mRNA and protein, which consequently declined when cells were treated with these inhibitors or arrested in the G(0) state of the cell cycle by serum starvation. We conclude that expression of the antiviral APOBEC3G editing enzyme is dynamically controlled by the PKCalpha/betaI/MEK/ERK protein kinase cascade in human T lymphocytes.

Highlights

APOBEC3G1 is a potent antiretroviral deoxycytidine deaminase that occurs in human T lymphocytes and macrophages and that lethally hypermutates the viral-negative DNA strand shortly after the DNA is synthesized by reverse transcriptase [1,2,3,4,5,6]
TNF-␣ had no effect on the APOBEC3G mRNA level, it was active in these cells as indicated by its ability to phosphorylate and activate p38 mitogen-activated protein kinase (MAPK)
APOBEC3G (Fig. 3), presumably because APOBEC3G mRNA and protein turn over relatively slowly (Figs. 2 and 4) [7, 10]. These studies provide initial evidence concerning the dynamic regulation of APOBEC3G mRNA and protein levels in the human T lymphocytic cell line H9

Summary

Introduction

APOBEC3G1 is a potent antiretroviral deoxycytidine deaminase that occurs in human T lymphocytes and macrophages and that lethally hypermutates the viral-negative DNA strand shortly after the DNA is synthesized by reverse transcriptase [1,2,3,4,5,6]. The PKC␣/␤I/MEK/ERK pathway controlled basal levels of APOBEC3G mRNA and protein, which declined when cells were treated with these inhibitors or arrested in the G0 state of the cell cycle by serum starvation.

Results

Conclusion