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1
* Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205; and
Zhejiang University, Zhejiang, China
APOBEC3G (A3G) has broad antiviral activity against retroviruses and hepatitis B virus. However, the role of IFNs in regulating A3G during innate immunity has not been established. In this study, we show that the A3G gene is uniquely regulated by IFNs in a cell type-dependent manner. A3G was up-regulated by IFN-
in liver cells and macrophages, but not in T lymphoid cells or epithelial 293T cells. In contrast, other IFN--stimulated genes such as dsRNA-activated protein kinase were induced in all these cells, suggesting additional cellular factors may regulate IFN--induced A3G expression. Consistent with this idea, IFN--mediated induction of A3G, but not other IFN--stimulated genes, was potently inhibited by the drug Rottlerin, through a mechanism independent of STAT1 activation. The canonical IFN--mediated pathway of gene transcription requires both STAT1 and STAT2. Surprisingly, induction of A3G was STAT1 independent, but STAT2 dependent in liver cells. However, STAT1 signaling was functional and required for IFN-
induction of A3G in these cells. Our results indicate that A3G may participate in antiviral cellular defenses through a novel IFN-mediated signaling pathway.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a grant from the National Institutes of Health (AI062644), a grant from the Johns Hopkins Center for AIDS Research, and funding from the National Science Foundation of China (NSFC-30425012) and Cheung Kong Scholars Program Foundation of the Chinese Ministry of Education (to X.-F.Y.).
2 Address correspondence and reprint requests to Dr. Xiao-Fang Yu, Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room E5148, Baltimore, MD 21205. E-mail address: xfyu{at}jhsph.edu
3 Abbreviations used in this paper: HIV-1, HIV type-1; HBV, hepatitis B virus; IRF, IFN regulatory factor; ISG, IFN-stimulated gene; ISGF3, ISG factor 3; ISRE, IFN-stimulated response element; LMP, low molecular mass polypeptide; PKC, protein kinase C; PKR, dsRNA-activated protein kinase; qRT-PCR, quantitative real-time RT-PCR; siRNA, small interfering RNA.
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