Regulation of Apobec3F and Human Immunodeficiency Virus Type 1 Vif by Vif-Cul5-ElonB/C E3 Ubiquitin Ligase

Liu, Bindong; Sarkis, Phuong Thi Nguyen; Luo, Kun; Yu, Yunkai; Yu, Xiao Fang

doi:10.1128/jvi.79.15.9579-9587.2005

Cited by 131 publications

(131 citation statements)

References 46 publications

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“…Lentiviruses such as HIV-1 and SIV encode the Vif protein, which assembles with cellular proteins Cul5, ElonginB and ElonginC to form an E3 ubiquitin ligase (Yu et al, 2003;Mehle et al, 2004;Kobayashi et al, 2005;Liu et al, 2005;Luo et al, 2005) that induces polyubiquitination and degradation of multiple APOBEC3 molecules (Conticello et al, 2003;Marin et al, 2003;Sheehy et al, 2003;Stopak et al, 2003;Yu et al, 2003;Liu et al, 2004;Mehle et al, 2004;Liu et al, 2005). Exogenous expression of APOBEC3G (A3G) and APOBEC3F (A3F) has also been found to reduce HBV core-associated DNA in transfected liver cell lines (Rosler et al, 2004;Turelli et al, 2004a,b;Noguchi et al, 2005;Suspene et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Cytidine deaminase APOBEC3B interacts with heterogeneous nuclear ribonucleoprotein K and suppresses hepatitis B virus expression

Zhang

Tian

et al. 2007

Cell Microbiol

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SummaryThe cytidine deaminase apolipoprotein B mRNA editing catalytic subunit-3 (APOBEC3) proteins have been identified as potent inhibitors of diverse retroviruses, retrotransposons and hepatitis B virus (HBV). The mechanism of APOBEC3 proteins in the control of HBV infection, however, is less clear. Here we report that APOBEC3B (A3B) displays dual inhibitory effects on both HBsAg and HBeAg expression as well as HBV core-associated DNA synthesis. Heterogeneous nuclear ribonucleoprotein K (hnRNP K), a positive regulator of HBV expression, has been identified as a major interaction partner of A3B protein. A3B protein inhibited the binding of hnRNP K to the enhancer II of HBV (Enh II), and S gene transcription of HBV. Moreover, A3B directly suppressed HBV S gene promoter activity. Individual variation in A3B expression was observed in both normal primary hepatocytes and liver tissues. Interestingly, A3B was able to inhibit CMV and SV40 promoter-mediated gene expression. In conclusion, A3B suppresses HBV replication in hepatocytes by inhibiting hnRNP K-mediated transcription and expression of HBV genes as well as HBV core DNA synthesis. In addition, A3B protein may be a broad antiviral host factor. Thus, regulated A3B expression may contribute to non-cytolytic HBV clearance in vivo.

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Section: Introductionmentioning

confidence: 99%

Cytidine deaminase APOBEC3B interacts with heterogeneous nuclear ribonucleoprotein K and suppresses hepatitis B virus expression

Zhang

Tian

et al. 2007

Cell Microbiol

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“…This single-stranded DNA, which has a minus sense, is synthesized using viral RNA as a template and is released from the DNA-RNA hybrid when the RNA is degraded by a ribonuclease H inherent in reverse transcriptase. Vif binds specifically to A3G and A3F and recruits a multisubunit ubiquitin ligase complex containing cullin 5 and elongins B-C that causes their polyubiquitination and proteasomal degradation, thereby ridding infected cells of these antiviral enzymes and precluding their incorporation into progeny virions (1,2,(11)(12)(13)(14)(15)(16).…”

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confidence: 99%

The Anti-HIV-1 Editing Enzyme APOBEC3G Binds HIV-1 RNA and Messenger RNAs That Shuttle between Polysomes and Stress Granules

Kozak

Marin

Rose

et al. 2006

Journal of Biological Chemistry

170

201

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Deoxycytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F) (members of the apolipoprotein B mRNA-editing catalytic polypeptide 3 family) have RNA-binding motifs, invade assembling human immunodeficiency virus (HIV-1), and hypermutate reverse transcripts. Antagonistically, HIV-1 viral infectivity factor degrades these enzymes. A3G is enzymatically inhibited by binding RNA within an unidentified large cytosolic ribonucleoprotein, implying that RNA degradation during reverse transcription may activate intravirion A3G at the necessary moment. We purified a biologically active tandem affinity-tagged A3G from human HEK293T cells. Mass spectrometry and coimmunoprecipitation from HEK293T and T lymphocyte extracts identified many RNAbinding proteins specifically associated with A3G and A3F, including poly(A)-binding proteins (PABPs), YB-1, Ro-La, RNA helicases, ribosomal proteins, and Staufen1. Most strikingly, nearly all A3G-associated proteins were known to bind exclusively or intermittently to translating and/or dormant mRNAs. Accordingly, A3G in HEK293T and T lymphocyte extracts was almost completely in A3G-mRNA-PABP complexes that shifted reversibly between polysomes and dormant pools in response to translational inhibitors. For example arsenite, which inhibits 5-cap-dependent translational initiation, shifted mRNA-A3G-PABP from polysomes into stress granules in a manner that was blocked and reversed by the elongation inhibitor cycloheximide. Immunofluorescence microscopy showed A3G-mRNA-PABP stress granules only partially overlapping with Staufen1. A3G coimmunoprecipitated HIV-1 RNA and many mRNAs. Ribonuclease released nearly all A3G-associated proteins, including A3G homo-oligomers and A3G-A3F hetero-oligomers, but the viral infectivity factor remained bound. Many proteins and RNAs associated with A3G are excluded from A3G-containing virions, implying that A3G competitively partitions into virions based on affinity for HIV-1 RNA.The viral infectivity factor (Vif) 4 encoded by human immunodeficiency virus type-1 (HIV-1) neutralizes a potent anti-HIV-1 defense system that occurs specifically in T lymphocytes and to a lesser degree in macrophages, thus explaining the efficient replication in T cells of wild-type HIV-1 but not HIV-1(⌬vif) that lacks a functional vif gene (1-4). This antiviral defense system involves the deoxycytidine deaminases APOBEC3G (A3G) and its paralog APOBEC3F (A3F) (members of the apolipoprotein B mRNA-editing catalytic polypeptide 3 family), each of which contains two RNA-binding motifs and incorporates into assembling HIV-1 capsids where they cause lethal dC-to-dU hypermutations in the single-stranded viral DNA that transiently forms during reverse transcription (1, 2, 4 -10). This single-stranded DNA, which has a minus sense, is synthesized using viral RNA as a template and is released from the DNA-RNA hybrid when the RNA is degraded by a ribonuclease H inherent in reverse transcriptase. Vif binds specifically to A3G and A3F and recruits a multisubunit ubiquitin ligase complex containing...

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“…The HIV-1 auxiliary protein Vif overcomes the antiviral activity of A3G and A3F by targeting both of these host factors for ubiquitin-dependent proteasomal degradation thereby preventing their incorporation into virions (17)(18)(19)(20)(21)(22)(23). Although they share some similar antiviral functions, A3G and A3F differ in their interactions with Vif, their overall antiviral activity in the absence of Vif, and their deaminase target site specificity (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). A3F is regarded as a less potent anti-HIV factor than A3G.…”

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Identification of Two APOBEC3F Splice Variants Displaying HIV-1 Antiviral Activity and Contrasting Sensitivity to Vif*

Wissing

Lobritz

Santiago

et al. 2010

Journal of Biological Chemistry

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Approximately half of all human genes undergo alternative mRNA splicing. This process often yields homologous gene products exhibiting diverse functions. Alternative splicing of APOBEC3G (A3G) and APOBEC3F (A3F), the major host resistance factors targeted by the HIV-1 protein Vif, has not been explored. We investigated the effects of alternative splicing on A3G/A3F gene expression and antiviral activity. Three alternatively spliced A3G mRNAs and two alternatively spliced A3F mRNAs were detected in peripheral blood mononuclear cells in each of 10 uninfected, healthy donors. Expression of these splice variants was altered in different cell subsets and in response to cellular stimulation. Alternatively spliced A3G variants were insensitive to degradation by Vif but displayed no antiviral activity against HIV-1. Conversely, alternative splicing of A3F produced a 37-kDa variant lacking exon 2 (A3F⌬2) that was prominently expressed in macrophages and monocytes and was resistant to Vif-mediated degradation. Alternative splicing also produced a 24-kDa variant of A3F lacking exons 2-4 (A3F⌬2-4) that was highly sensitive to Vif. Both A3F⌬2 and A3F⌬2-4 displayed reduced cytidine deaminase activity and moderate antiviral activity. These alternatively spliced A3F gene products, particularly A3F⌬2, were incorporated into HIV virions, albeit at levels less than wild-type A3F. Thus, alternative splicing of A3F mRNA generates truncated antiviral proteins that differ sharply in their sensitivity to Vif.Human A3G and A3F belong to the family of APOBEC3 cytidine deaminases that exert antiviral activity against diverse exogenous viruses, including HIV-1 (reviewed in Ref. 1). In humans, seven A3 proteins (designated A3A, A3B, A3C, A3DE, A3F, A3G, and A3H) are tandemly arrayed on chromosome 22 (2, 3). In contrast, mice have only a single A3 gene (mA3) located on a syntenic region of chromosome 15 (4, 5). Despite extensive evolutionary expansion of this locus, expression of human A3 genes remains tightly regulated and tissue-specific (3). Alternative splicing might represent one mechanism whereby the level and action of the A3 family is modulated.Alternative splicing of pre-mRNA represents a major mechanism for expanding gene function and diversity (6, 7). Approximately 40 -60% of human genes are alternatively spliced (8 -13), and about one-quarter of this alternative splicing is conserved across species (11). Read-through alternative splicing of feline A3 genes generates a novel functional isoform (4), whereas alternative splicing and/or diminished expression of mA3 impairs the ability of certain strains of mice to recover from Friend virus complex infection (Rfv3) (14, 15). In humans, gene polymorphisms and alternative splicing of A3H result in diverse effects on antiviral activity (16). However, it is not known whether A3G and A3F, the major anti-HIV A3 enzymes and targets of HIV Vif, are functionally regulated by alternative splicing.A3G and A3F contain dual conserved catalytic domains located in the N-and C-terminal regions termed...

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Regulation of Apobec3F and Human Immunodeficiency Virus Type 1 Vif by Vif-Cul5-ElonB/C E3 Ubiquitin Ligase

Cited by 131 publications

References 46 publications

Cytidine deaminase APOBEC3B interacts with heterogeneous nuclear ribonucleoprotein K and suppresses hepatitis B virus expression

Cytidine deaminase APOBEC3B interacts with heterogeneous nuclear ribonucleoprotein K and suppresses hepatitis B virus expression

The Anti-HIV-1 Editing Enzyme APOBEC3G Binds HIV-1 RNA and Messenger RNAs That Shuttle between Polysomes and Stress Granules

Identification of Two APOBEC3F Splice Variants Displaying HIV-1 Antiviral Activity and Contrasting Sensitivity to Vif*

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