STAT1-Independent Cell Type-Specific Regulation of Antiviral APOBEC3G by IFN-α

Sarkis, Phuong Thi Nguyen; Shi, Ying; Xu, Rongzhen; Yu, Xiao Fang

doi:10.4049/jimmunol.177.7.4530

Cited by 87 publications

(91 citation statements)

References 53 publications

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“…These findings are in very close agreement with those reported recently by Koning et al (47), who found that A3G protein levels did not increase in IFN␣-treated CD4 ϩ T cells although they displayed an IFN␣-mediated induction of A3G mRNA, whereas A3G protein levels did increase significantly in MDMs treated with IFN␣. Thus, our data are consistent with previous reports that IFN␣ leads to higher steady state A3G protein levels in MDMs (47,75,76) but not in CD4 ϩ T cells (47,76).…”

Section: Discussionsupporting

confidence: 83%

Innate Immune Signaling Induces High Levels of TC-specific Deaminase Activity in Primary Monocyte-derived Cells through Expression of APOBEC3A Isoforms

Thielen

McNevin

McElrath

et al. 2010

Journal of Biological Chemistry

105

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In HIV-1-infected individuals, G-to-A hypermutation is found in HIV-1 DNA isolated from peripheral blood mononuclear cells (PBMCs). These mutations are thought to result from editing by one or more host enzymes in the APOBEC3 (A3) family of cytidine deaminases, which act on CC (APOBEC3G) and TC (other A3 proteins) dinucleotide motifs in DNA (edited cytidine underlined). Although many A3 proteins display high levels of deaminase activity in model systems, only low levels of A3 deaminase activity have been found in primary cells examined to date. In contrast, here we report high levels of deaminase activity at TC motifs when whole PBMCs or isolated primary monocyte-derived cells were treated with interferon-␣ (IFN␣) or IFN␣-inducing toll-like receptor ligands. Induction of TC-specific deaminase activity required new transcription and translation and correlated with the appearance of two APOBEC3A (A3A) isoforms. Knockdown of A3A in monocytes with siRNA abolished TC-specific deaminase activity, confirming that A3A isoforms are responsible for all TC-specific deaminase activity observed. Both A3A isoforms appear to be enzymatically active; moreover, our mutational studies raise the possibility that the smaller isoform results from internal translational initiation. In contrast to the high levels of TC-specific activity observed in IFN␣-treated monocytes, CC-specific activity remained low in PBMCs, suggesting that A3G deaminase activity is relatively inhibited, unlike that of A3A. Together, these findings suggest that deaminase activity of A3A isoforms in monocytes and macrophages may play an important role in host defense against viruses. A33 proteins are cytidine deaminases that are capable of inhibiting replication of retroviruses, DNA viruses, and retroelements (reviewed in Refs. 1-3). The seven A3 proteins in the human genome share a strong preference for deaminating cytidines that are in a CC or TC context in single-stranded DNA (edited cytidine underlined). Although APOBEC3G (A3G), the best understood A3 protein, acts preferentially on CC motifs, the six other human A3 proteins display varying degrees of preference for TC motifs (4 -13). Because other cytidine deaminases, such as activation-induced deaminase and APOBEC1, either display a strong preference for editing deoxycytidines in other dinucleotide contexts or act on TC motifs in RNA (4), mutations that arise in a CC or TC context in DNA constitute signatures of editing by A3 proteins.Much headway has been made in understanding how A3 proteins act on HIV-1 DNA, in part through transfection of A3 plasmids into human epithelium-derived cell lines, such as 293T or HeLa cells, which lack significant endogenous expression of most A3 proteins. From such studies, A3G and APOBEC3F (A3F) are known to be packaged into virus particles when the HIV-1 Vif protein is not expressed and to cause a substantial reduction in virus infectivity (5, 12, 14 -16). Reduced virus infectivity results in part from non-enzymatic inhibition of reverse transcription by A3G and A3F (17-2...

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Section: Discussionsupporting

confidence: 83%

Innate Immune Signaling Induces High Levels of TC-specific Deaminase Activity in Primary Monocyte-derived Cells through Expression of APOBEC3A Isoforms

Thielen

McNevin

McElrath

et al. 2010

Journal of Biological Chemistry

105

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“…Previous reports have described the capacity of STAT2 and IRF9 to activate gene transcription independently of STAT1 [20][21][22][23][24]. However, none of these studies have linked the activation of the STAT2/IRF9 pathway to the specific synergistic action of IFNβ and TNFα.…”

Section: Rsv Interferes With the Expression Of Duox2mentioning

confidence: 85%

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

et al. 2013

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Airway epithelial cells are key initial innate immune responders in the fight against respiratory viruses, primarily via the secretion of antiviral and proinflammatory cytokines that act in an autocrine/paracrine fashion to trigger the establishment of an antiviral state. It is currently thought that the early antiviral state in airway epithelial cells primarily relies on IFNβ secretion and the subsequent activation of the interferon-stimulated gene factor 3 (ISGF3) transcription factor complex, composed of STAT1, STAT2 and IRF9, which regulates the expression of a panoply of interferon-stimulated genes encoding proteins with antiviral activities. However, the specific pathways engaged by the synergistic action of different cytokines during viral infections, and the resulting physiological outcomes are still ill-defined. Here, we unveil a novel delayed antiviral response in the airways, which is initiated by the synergistic autocrine/paracrine action of IFNβ and TNFα, and signals through a non-canonical STAT2-and IRF9-dependent, but STAT1-independent cascade. This pathway ultimately leads to the late induction of the DUOX2 NADPH oxidase expression. Importantly, our study uncovers that the development of the antiviral state relies on DUOX2-dependent H 2 O 2 production. Key antiviral pathways are often targeted by evasion strategies evolved by various pathogenic viruses. In this regard, the importance of the novel DUOX2-dependent antiviral pathway is further underlined by the observation that the human respiratory syncytial virus is able to subvert DUOX2 induction.

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“…Increasing number of studies show that other types of STAT complexes can be formed in response to IFNs (7). Several type I IFN-mediated STAT2-dependent, but STAT1-independent, mechanisms were reported (25)(26)(27)(28)(29)(30). Because STAT2 is the only member of the STAT family without DNA-binding activity, it can act as a transcription factor only when complexed to other STATs or proteins (31).…”

Section: Discussionmentioning

confidence: 99%

IFR-9/STAT2 Functional Interaction Drives Retinoic Acid–Induced Gene G Expression Independently of STAT1

et al. 2009

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Retinoic acid-induced gene G (RIG-G), a gene originally identified in all-trans retinoic acid-treated NB4 acute promyelocytic leukemia cells, is also induced by IFNA in various hematopoietic and solid tumor cells. Our previous work showed that RIG-G possessed a potent antiproliferative activity. However, the mechanism for the transcriptional regulation of RIG-G gene remains unknown. Here, we report that signal transducer and activator of transcription (STAT) 2 together with IFN regulatory factor (IRF)-9 can effectively drive the transcription of RIG-G gene by their functional interaction through a STAT1-independent manner, even without the tyrosine phosphorylation of STAT2. The complex IRF-9/STAT2 is both necessary and sufficient for RIG-G gene expression. In addition, IRF-1 is also able to induce RIG-G gene expression through an IRF-9/STAT2-dependent or IRF-9/ STAT2-independent mechanism. Moreover, the induction of RIG-G by retinoic acid in NB4 cells resulted, to some extent, from an IFNA autocrine pathway, a finding that suggests a novel mechanism for the signal cross-talk between IFNA and retinoic acid. Taken together, our results provide for the first time the evidence of the biological significance of IRF-9/STAT2 complex, and furnish an alternative pathway modulating the expression of IFN-stimulated genes, contributing to the diversity of IFN signaling to mediate their multiple biological properties in normal and tumor cells. [Cancer Res 2009;69(8):3673-80]

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STAT1-Independent Cell Type-Specific Regulation of Antiviral APOBEC3G by IFN-α

Cited by 87 publications

References 53 publications

Innate Immune Signaling Induces High Levels of TC-specific Deaminase Activity in Primary Monocyte-derived Cells through Expression of APOBEC3A Isoforms

Innate Immune Signaling Induces High Levels of TC-specific Deaminase Activity in Primary Monocyte-derived Cells through Expression of APOBEC3A Isoforms

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

IFR-9/STAT2 Functional Interaction Drives Retinoic Acid–Induced Gene G Expression Independently of STAT1

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