Deaminase-Independent Inhibition of Parvoviruses by the APOBEC3A Cytidine Deaminase

Narvaiza, Iñigo; Linfesty, Daniel C; Greener, Benjamin N.; Hakata, Yoshiyuki; Pintel, David J.; Logue, Eric C.; Landau, Nathaniel R.; Weitzman, Matthew D.

doi:10.1371/journal.ppat.1000439

Cited by 125 publications

(143 citation statements)

References 77 publications

(144 reference statements)

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“…Previous studies showed that increased amounts of transfected pA3A increases antiviral functions of A3A in vitro. 13,23 We find that higher expression of A3A also causes higher levels of RNA editing. Thus, there is a possibility of a correlation between RNA editing of host transcripts and the antiviral activity of A3A.…”

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confidence: 72%

“…[12][13][14][15][16][17][18][19] The virusrestricting functions of A3A are typically demonstrated by reduced infectivity of the virus upon exogenous co-expression of the plasmids encoding the enzyme and viruses in a cell line such as HEK293T human embryonic kidney cells. [12][13][14][15][16][17]19 Although A3A's cytidine deaminase function is essential for its antiviral activities, 6,12,20,21 the mechanism by which A3A inhibits viruses is not understood well. A3A efficiently mutates single stranded DNA oligonucleotides in vitro 11 and transfected plasmid DNAs in overexpression systems.…”

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confidence: 99%

“…22 However, DNA mutations in the infectious agents restricted by A3A could not be conclusively demonstrated. 12,13,17,19,23 In this study, we examine the impact of A3A overexpression in the human transcriptome by characterizing the transcriptome wide C > U RNA editing and gene expression changes upon exogenous expression in HEK293T cells. Our results show an unprecedented extent of RNA editing by A3A.…”

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confidence: 99%

“…Cellular RNA editing model of viral restriction is particularly relevant for A3A, where mutations in the inhibited virus DNAs have yet to be conclusively demonstrated. 12,13,17,19,23 Nevertheless, a direct link between host gene RNA editing and antiviral function of A3A remains to be demonstrated.…”

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confidence: 99%

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Transient overexpression of exogenous APOBEC3A causes C-to-U RNA editing of thousands of genes

et al. 2016

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APOBEC3A cytidine deaminase induces site-specific C-to-U RNA editing of hundreds of genes in monocytes exposed to hypoxia and/or interferons and in pro-inflammatory macrophages. To examine the impact of APOBEC3A overexpression, we transiently expressed APOBEC3A in HEK293T cell line and performed RNA sequencing. APOBEC3A overexpression induces C-to-U editing at more than 4,200 sites in transcripts of 3,078 genes resulting in protein recoding of 1,110 genes. We validate recoding RNA editing of genes associated with breast cancer, hematologic neoplasms, amyotrophic lateral sclerosis, Alzheimer disease and primary pulmonary hypertension. These results highlight the fundamental impact of APOBEC3A overexpression on human transcriptome by widespread RNA editing.

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confidence: 72%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Transient overexpression of exogenous APOBEC3A causes C-to-U RNA editing of thousands of genes

et al. 2016

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“…Expression of a functional HIV-1 Vif protein counteracts the antiviral effects of A3G and A3F by recruiting them to the proteasome for degradation, thereby preventing their incorporation into viral particles (14, 24 -30). Although HIV-1 is the best studied A3 viral target, studies using A3 transfection systems have demonstrated that one or more human A3 proteins are also able to inhibit replication of other pathogenic human viruses, including HIV-2 (31), hepatitis B virus (32)(33)(34)(35), and parvoviruses (36,37).…”

Section: A3mentioning

confidence: 99%

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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Host apolipoprotein b messenger RNA-editing enzyme catalytic polypeptide-like 3G is an innate defensive factor and drug target against hepatitis C virus

Peng

Zhao

et al. 2011

Hepatology

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Host cellular factor apolipoprotein B messenger RNA (mRNA)-editing enzyme catalytic polypeptide-like 3G (hA3G) is a cytidine deaminase that inhibits a group of viruses including human immunodeficiency virus-1 (HIV-1). In the continuation of our research on hA3G, we found that hA3G stabilizing compounds significantly inhibited hepatitis C virus (HCV) replication. Therefore, this study investigated the role of hA3G in HCV replication. Introduction of external hA3G into HCV-infected Huh7.5 human hepatocytes inhibited HCV replication; knockdown of endogenous hA3G enhanced HCV replication. Exogenous HIV-1 virion infectivity factor (Vif) decreased intracellular hA3G and therefore enhanced HCV proliferation, suggesting that the presence of Vif might be an explanation for the HIV-1/HCV coinfection often observed in HIV-1(1) individuals. Treatment of the HCV-infected Huh7.5 cells with RN-5 or IMB-26, two known hA3G stabilizing compounds, increased intracellular hA3G and accordingly inhibited HCV replication. The compounds inhibit HCV through increasing the level of hA3G incorporated into HCV particles, but not through inhibiting HCV enzymes. However, G/A hypermutation in the HCV genome were not detected, suggesting a new antiviral mechanism of hA3G in HCV, different from that in HIV-1. Stabilization of hA3G by RN-5 was safe in vivo. Conclusion: hA3G appears to be a cellular restrict factor against HCV and could be a potential target for drug discovery.

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Deaminase-Independent Inhibition of Parvoviruses by the APOBEC3A Cytidine Deaminase

Cited by 125 publications

References 77 publications

Transient overexpression of exogenous APOBEC3A causes C-to-U RNA editing of thousands of genes

Transient overexpression of exogenous APOBEC3A causes C-to-U RNA editing of thousands of genes

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

Host apolipoprotein b messenger RNA-editing enzyme catalytic polypeptide-like 3G is an innate defensive factor and drug target against hepatitis C virus

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