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Journal of Virology, June 2008, p. 5636-5642, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.00287-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Comparison of Cellular Ribonucleoprotein Complexes Associated with the APOBEC3F and APOBEC3G Antiviral Proteins{triangledown}

Sarah Gallois-Montbrun,1 Rebecca K. Holmes,1 Chad M. Swanson,1 Mireia Fernández-Ocaña,2 Helen L. Byers,3 Malcolm A. Ward,3 and Michael H. Malim1*

Department of Infectious Diseases, King's College London School of Medicine, London SE1 9RT, United Kingdom,1 MRC Centre for Neurodegeneration Research,2 Proteome Sciences plc, Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom3

Received 8 February 2008/ Accepted 17 March 2008


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ABSTRACT
 
The human apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3F (APOBEC3F [A3F]) and A3G proteins are effective inhibitors of infection by various retroelements and share ~50% amino acid sequence identity. We therefore undertook comparative analyses of the protein and RNA compositions of A3F- and A3G-associated ribonucleoprotein complexes (RNPs). Like A3G, A3F is found associated with a complex array of cytoplasmic RNPs and can accumulate in RNA-rich cytoplasmic microdomains known as mRNA processing bodies or stress granules. While A3F RNPs display greater resistance to disruption by RNase digestion, the major protein difference is the absence of the Ro60 and La autoantigens. Consistent with this, A3F RNPs also lack a number of small polymerase III RNAs, including the RoRNP-associated Y RNAs, as well as 7SL RNA. Alu RNA is, however, present in A3F and A3G RNPs, and both proteins suppress Alu element retrotransposition. Thus, we define a number of subtle differences between the RNPs associated with A3F and A3G and speculate that these contribute to functional differences that have been described for these proteins.


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TEXT
 
The apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) proteins constitute a family of cell-encoded polynucleotide cytidine deaminases with diverse biological functions ranging from site-specific mRNA editing and antibody diversification to the inhibition of retrovirus infection and/or retrotransposition (5, 13, 15, 24). The execution of these activities is frequently associated with RNA/DNA editing (also called hypermutation when occurring at excessive levels), though deamination-independent effects have also been described (3, 4, 6, 10, 16, 19-21, 23, 27, 34, 35, 39, 45, 46, 57, 67, 71). Because these protein mutagens are constitutively expressed under physiological conditions, it stands to reason that their respective capacities to edit nucleic acids must be regulated to avert deleterious mutations arising as well as to select intended substrates in the appropriate temporal and spatial manner. Indeed, evidence is accumulating that APOBEC1, AID (activation-induced deaminase), APOBEC3G (A3G), and A3F are subject to cellular regulatory mechanisms (5, 7, 8, 10, 15, 56, 59). Notably, such mechanisms stand in contrast to the virus-driven negative regulation of the antiviral proteins, A3G and A3F, which is mediated by the Vif proteins of human immunodeficiency virus (HIV) and simian immunodeficiency virus (4, 17, 32, 35, 36, 53, 65, 72) through the induction of proteasomal degradation following the recruitment of the cullin5-elonginB/C-Rbx ubiquitin ligase to A3F/G (12, 33, 38, 40, 41, 54, 58, 68, 69).

We and others have started to address the regulation of A3G by examining its interactions with cellular factors. Biochemical studies have demonstrated its association with RNase-sensitive ribonucleoprotein (RNP) complexes and, accordingly, with many cellular RNA binding proteins, as well as certain mRNAs and small noncoding RNAs (10, 11, 18, 29, 31, 61, 63, 64). Together with subcellular localization experiments, these studies give a picture whereby A3G appears to be dynamically associated with diverse RNPs such as ribosomes, miRNA-induced silencing complexes (miRISCs), and RoRNPs (which contain the Ro60 autoantigen) and with important sites of RNA function, metabolism, and accumulation such as polysomes, processing bodies (PBs), stress granules (SGs), and Staufen granules (2, 11, 18, 31, 49, 64).

A3F and A3G are closely related in terms of protein sequence and are both marked inhibitors of vif-deficient HIV type 1 (HIV-1) infection (4, 28, 32, 53, 65, 72). Nevertheless, clear functional differences are evident: (i) the anti-HIV-1 potency of A3F is significantly less than that of A3G (23, 70), (ii) the levels of cytidine-to-uridine mutation detected in nascent HIV-1 cDNAs during virus infection in the presence of A3F are lower than for A3G (4, 72), (iii) the editing-independent anti-HIV-1 effect of A3F may be more robust than that of A3G (23), (iv) the preferred dinucleotide substrate for A3F is TpC but CpC for A3G (edited cytidine underlined) (4, 32, 65), and (v) there are differences in the specific residues in HIV-1 Vif proteins that regulate A3F versus A3G (51, 55, 60). Accordingly, we wished to characterize A3F-containing RNPs and to identify similarities and differences with A3G RNPs that might explain these functional differences.

We used a previously described affinity purification strategy whereby a tandem-affinity purification (TAP) tag was appended to the amino terminus of A3F (without disturbing anti-HIV-1 activity [data not shown]) and stably expressing CEM-SS cells were created by retroviral vector-mediated transduction (18): these cells were used as the level of endogenous A3F expression is low (4). Cell lysates were prepared from cultures of ~4 x 108 cells as well as from CEM-SS/NTAP-A3G cells and the A3F/G complexes isolated using the Interplay mammalian TAP system (Stratagene). Proteins recovered from the second elution were adjusted to give roughly equivalent loading levels, resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) on a 10% gel, and stained with silver. As seen in Fig. 1A, lanes 1 and 2, the profiles of proteins copurifying with A3F and A3G are very similar. One clear difference between the profiles was the apparent absence of the band at ~54 kDa from the A3F sample, which corresponds to the La and Ro60 autoantigens (18); immunoblotting of these samples with a Ro60-specific antibody confirmed the absence of Ro60 from A3F RNPs (data not shown).


Figure 1
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  		FIG. 1. Purification and coimmunoprecipitation of proteins associated with A3F RNPs. (A) TAP tag purification of A3F/G RNPs from 293T cells. Cultures of CEM-SS cells stably expressing NTAP-tagged A3F or A3G were prepared and treated with RNase A (Sigma) for 1 h at room temperature (lanes 3 and 4) or left untreated (lanes 1 and 2). NTAP-A3F/G complexes were purified using streptavidin binding peptide-coated beads followed by calmodulin binding peptide-coated beads, final samples were resolved by SDS-PAGE, and the bands were visualized by silver staining. The previously determined compositions of some prominent bands (18) are indicated to the left, as are the bands corresponding to A3F/G. The bands indicated to the right (•) were excised for MS analyses (protein groupings in Table 1). (B and C) Coimmunoprecipitation of cellular proteins with A3F. 293T cells cotransfected with 2 µg pA3F-HA or pA3G-HA plus 3 µg (B) or 2 µg (C) of vectors expressing myc- or vesicular stomatitis virus G-tagged versions of cellular proteins were lysed and immunoprecipitated with the anti-HA 12CA5 (B) or anti-myc 9E10 (C) antibodies (18). When indicated, the immunoprecipitates were treated with an RNase mixture (DNase-free; Roche) (w/o, without RNase treatment). Samples were analyzed by immunoblotting using the indicated primary antibodies, horseradish peroxidase-conjugated secondary antibodies, and enhanced chemiluminescence. In the La analyses, a background band (indicated with an asterisk) of mobility slightly slower than that of tagged La was consistently detected. IP, immunoprecipitation.

Previous studies have demonstrated that the majority of the protein interactions with A3G are sensitive to disruption by treatment with RNase, indicating that RNA plays an important "bridging" or facilitating role in the formation of the RNPs and that many RNP components are RNA binding proteins (11, 18, 31, 64). We repeated this assessment here by treating NTAP-A3F/G-containing lysates with 10 µg/ml RNase A for 60 min prior to isolation of the A3F/G complexes and SDS-PAGE (Fig. 1A, lanes 3 and 4). As demonstrated earlier (18), the majority of A3G-associated proteins were displaced by RNA digestion: in marked contrast, a significant number of proteins remained associated with A3F. This result is consistent with a previous observation that employed sucrose gradient analyses to show that the reduction in the density of A3F RNPs following RNase treatment was relatively minor in comparison to what was seen for similarly treated A3G RNPs (63). Whether relative insensitivity to RNase digestion reflects the existence of numerous RNA-independent interactions between A3F and other cellular proteins or the "shielding" of RNA from enzymatic digestion remains to be resolved. Given the large number of proteins detected in Fig. 1A, lane 4, we currently favor the latter hypothesis.

Of the proteins remaining associated with A3F following RNase digestion, it was possible that a number may not have been identified in previous proteomic analyses of A3G RNPs, particularly as some of the prominent bands differ from those seen in lanes 1 and 2 of Fig. 1A. We therefore excised five such bands (indicated to the right of lane 4), digested them with trypsin, and identified the resulting peptides by mass spectrometry (18, 66) and subsequent database searching using Mascot software. As displayed in Table 1, many cellular RNA binding proteins such as hnRNP proteins and ribosomal proteins as well as some cytoskeletal and mitochondrial proteins were found. The majority of these proteins have in fact been previously identified as constituents of A3G RNPs in three independent analyses (11, 18, 31). Thus, this analysis confirms the very similar compositions of A3F and A3G RNPs but failed to find proteins that are uniquely present in A3F RNPs.


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  		TABLE 1. Mass spectrometry analysis of proteins associated with NTAP-A3F complexes following RNase A treatmenta

We next used cotransfection of 293T cells and coimmunoprecipitation with hemagglutinin (HA)-epitope tagged A3F/G proteins to examine interactions with selected RNA binding proteins (Fig. 1B). The interactions between Mov10, an RNA helicase found in PBs and miRISC complexes (22, 49), or poly(A)-binding protein, cytoplasmic 1 (PABC1) and A3F/G were similar and were sensitive to RNase. In contrast, and in agreement with the TAP tag results, the Ro60 and La proteins were found in association with A3G but not with A3F. One curiosity of these data is that A3F-HA migrates more rapidly in these gels than A3G-HA, yet this order is reversed for NTAP-tagged proteins: although we do not understand the basis for this, we noted that the effects were consistent and we confirmed the construction of plasmids by sequencing.

In a second set of assays, we then used a series of myc epitope-tagged proteins to coimmunoprecipitate the HA-tagged A3F/G proteins (Fig. 1C). In this instance, we focused on three proteins known to be constituents of miRISCs, the RNPs that mediate mRNA silencing, namely, YB-1, argonaute 1 (Ago1), and Ago2 (22). As previously established for A3G, A3F also interacts with these proteins (but not with the green fluorescent protein control) and does so in an RNase-insensitive manner (we did note that YB-1's association with A3G is partially sensitive to RNase). Though not yet resolved, resistance to RNase could be indicative of either direct protein-protein interactions or RNP conformations that protect bridging RNAs from susceptibility to digestion. Nevertheless, these findings further hint at an intersection between APOBEC protein function and RNA-silencing pathways (25).

Earlier imaging-based studies were used to develop further the model that A3G is dynamically associated with different RNPs and can localize to discrete cytosolic microdomains involved in RNA metabolism, function, and storage (18, 64). We therefore carried out similar studies using confocal microscopy and yellow fluorescent protein-tagged A3F, various other fluorescent protein labeled- or epitope-tagged proteins, and transiently transfected HeLa cells (Fig. 2). At 37°C, A3F colocalizes closely with A3G both throughout the cytoplasm, which we have previously designated polysomal localization, and to a number of discrete cytosolic sites (Fig. 2A). Double-label experiments where Mov10, Ago2, YB-1, and the mRNA-decapping enzyme Dcp1a were detected clearly define these sites as PBs (Fig. 2B to E), as noted earlier by others (37, 64). Transiently subjecting such cultures to 44°C induces the rapid accumulation of A3G and many cellular RNA binding proteins such as PABC1 and TIA-1 into larger, somewhat irregular granules called SGs (18). As expected, and consistent with its association with a heavily overlapping set of RNPs, A3F also redistributed and localized to SGs under these conditions (Fig. 2F and G).


Figure 2
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  		FIG. 2. Localization of A3F to cytoplasmic microdomains. HeLa cells coexpressing yellow fluorescent protein-tagged A3F (YFP-A3F) (left) and the indicated P-body markers myc-A3G (A), myc-Mov10 (B), mRFP-Dcp1a (C), myc-Ago2 (D), or myc-YB-1 (E) or the SG markers cherry-PABC1 (F) or cherry-TIA-1 (G) (middle) were cultured at 37°C or shocked at 44°C for 30 min prior to fixation and direct visualization (C, F, and G) or staining with the 9E10 antibody and a mouse-specific secondary antibody conjugated to Alexa Fluor 594 dye (A, B, D, and E). Samples were viewed by confocal microscopy, and merged views are displayed on the right. Bars = 10 µm.

The presence of any given RNA in A3F/G RNPs could have various consequences: for instance, their function or localization could be regulated, they could be substrates for editing, or they could be structural scaffolds. This question has begun to be addressed for A3G, where associations with HIV-1 RNA, certain mRNAs (such as that encoding A3G itself), and various small noncoding polymerase III RNAs, including those of the L1-dependent retrotransposable Alu and human Y RNA elements, as well as the 7SL RNA of the signal recognition particle, have been described (11, 29, 31, 61). Moreover, the binding of 7SL RNA, which is itself packaged into HIV-1 particles (47), has been ascribed a role in the virion encapsidation of A3G by some (61) but not by others (29). Because the major protein difference between A3F RNPs and A3G RNPs is the absence of the Ro60 and La proteins (Fig. 1), and these form RNPs containing Y RNAs (50), we assessed the potential association(s) of 7SL, Alu, and Y RNAs with HA-tagged A3F/G proteins. 293T cells were transfected with HA-tagged A3F/G expression vectors, whole-cell lysates prepared and precleared overnight using an irrelevant monoclonal antibody, and A3F/G RNPs immunoprecipitated with the 12CA5 HA-specific monoclonal antibody. Bound RNAs were recovered (miRNAeasy mini kit with on-column DNase digestion; Qiagen), amplified by semiquantitative reverse transcription-PCR using the SuperScript III one-step reverse transcription-PCR system with platinum Taq DNA polymerase (Invitrogen) (refer to Fig. 3 legend), and visualized by agarose gel electrophoresis and ethidium bromide staining (input lysates served as positive controls and reactions without reverse transcriptase as negative controls) (Fig. 3A). Quantitative immunoblotting of precipitated samples with Odyssey infrared imaging indicated that the efficiencies of A3F and A3G immunoprecipitation were similar (1.5- to 2.5-fold difference) (Fig. 3B).


Figure 3
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  		FIG. 3. A3F interacts with Alu RNA and inhibits Alu and LINE-1 retrotransposition. (A) Interaction of specific RNAs with A3F and A3G. 293T cells expressing A3F-HA or A3G-HA were lysed and subjected to immunoprecipitation with an anti-HA antibody; then, associated RNAs were purified and the indicated RNAs were detected by semiquantitative reverse transcription-PCR (RT-PCR) (cDNA synthesis at 55°C for 30 min; denaturation at 95°C for 2 min; 25 amplification cycles of 95°C for 15 s, 56°C for 30 s, and 68°C for 1 min; and a final extension step at 68°C for 5 min) and agarose gel electrophoresis. The primers for Y1, Y4, 7S, Alu, and {alpha}-tubulin RNA have been described previously (11, 29, 47), and those for A3G were 5'-TATGAGGTCACCTGGTTCATATCCTGGAGCCCC and 5'-GGGGCTCCAGGAGGTGAGGCAGGTAACCCTGTA, those for A3F were 5'-CCCTGCCCGGACTCTGTGGCGAAGCTG and 5'-GAGGAAGCACCTTTGTGCATGACAATGGGT, and those for GAPDH were 5'-AGCCACATACCAGGAAATG and 5'-GGTCTCCTCTGACTTCAAC. The sole exceptions were the Alu samples, where the cells were cotransfected with pAlu-neoTet (14). IP, immunoprecipitation. (B) Immunoprecipitation of A3F and A3G. To ensure similar efficiencies of immunoprecipitation, samples from panel A were immunoblotted using the 12CA5 antibody followed by an IRDye800CW-labeled secondary antibody and then quantified using Odyssey infrared imaging (Li-Cor Biosciences). (C) Inhibition of Alu and LINE-1 retrotransposition. Thirty-five-millimeter-diameter HeLa-HA cell monolayers (26) were cotransfected with 0.5 µg pA3F-HA, pA3G-HA, or empty vector together with 1.5 µg pAlu-neoTet plus 0.5 µg pCEP-5UTR-ORF2-{Delta}neo (1) or 1.5 µg pJM101/L1.3 (42) to assess Alu or LINE-1 retrotransposition, respectively. Cultures were placed under G418 selection for 10 to 12 days and the colonies counted to represent the numbers of retrotransposition events. The mean and standard deviation values for three experiments that were each performed in duplicate are shown. (Bottom) Lysates collected 24 h after transfection were analyzed by immunoblotting as for Fig. 1 to confirm A3F/G expression.

Substantial differences in associated small RNAs were evident: whereas A3G RNPs contained Y1, Y4, 7SL, and Alu RNAs (Fig. 3A, upper four panels) (as well as Y2 and Y3 RNA [data not shown]), only Alu RNA was readily seen in the equivalent A3F sample (fourth panel) (Y4 was sometimes detected in A3F samples in trace amounts). As expected, both proteins were found in association with their cognate mRNAs (fifth and sixth panels). Our findings with A3G are therefore in close general agreement with previous analyses (11, 29, 61), but those for A3F differ from a recent report suggesting that the Y, 7SL, and Alu RNAs also associate with A3F RNPs (62). Though the basis for such differences is not yet known, we note that the absence of Y RNAs in A3F RNPs is consistent with the absence of the Ro60 antigen from these complexes (Fig. 1A). Whether the lack of 7SL RNA in A3F RNPs is caused by the absence of certain RNPs or by the inability of A3F to bind this RNA directly remains to be determined. Similarly, it is not yet known if Alu RNA binds A3F/G directly or whether such interactions are indirect.

The recruitment of Alu RNA into cytoplasmic A3G RNPs is thought to inhibit Alu retrotransposition by precluding interactions with the trans-acting ORF2 protein of long interspersed nuclear element 1 (LINE-1) elements (11). Since we found Alu RNA to be associated with cytoplasmic A3F RNPs (Fig. 3A), we asked whether A3F can also inhibit retrotransposition. To do this, we used established marker gene assays in which successful retrotransposition is registered by the removal of an intron from a neomycin phosphotransferase gene that is flanked by the natural terminal sequence elements of the transposon, its ensuing integration into cellular DNA, and the acquisition of G418 resistance (14, 43). HeLa-HA cells were transfected with HA-tagged A3F/G vectors and either pJM101/L1.3 (to test for autonomous LINE-1 transposition) or pAlu-neoTet and pCEP-5'UTR-ORF2-{Delta}neo (to test for nonautonomous Alu transposition), and G418-resistant colonies stained and counted 10 to 12 days later (Fig. 3C). As noted in some reports (9, 26, 30, 44, 57), relatively modest decreases in LINE-1 retrotransposition to 30 to 40% of the control level could be seen for A3F and A3G, whereas Alu retrotransposition was reduced substantially to ~5% by A3G (11, 26). Likewise, we also found that A3F inhibited Alu transposition relatively efficiently, to ~10% of the control. While the extent of suppression is greater than that noted by others (26), we consider our findings to be consistent with the presence of Alu RNA in A3F RNPs (Fig. 3A) and with the many commonalities we have described between A3F and A3G RNPs.

In sum, we have demonstrated that A3F, like A3G, not only is incorporated into a complex set of RNPs in metabolically active cells (Fig. 1A) but also localizes to cytosolic sites of mRNA metabolism and storage (Fig. 2). The contents of these A3F/G RNPs overlap extensively, with many of the constituent proteins being the same RNA binding proteins (Fig. 1). These proteins play a multitude of roles in the function, regulation, and fate of RNA, though the interaction with miRISC components is noteworthy in light of A3G's ability to modulate miRNA-mediated translational repression and mRNA turnover (25). Understanding the functional significance of the interactions between A3F/G and various RNP complexes (as well as the levels of diversity and distinctiveness) therefore represents a challenge for the future.

Despite all the shared features between A3F and A3G RNPs, some differences were identified. Though we do not yet appreciate the mechanistic basis, A3F RNPs are noticeably more resilient to RNase-mediated disruption than counterpart A3G RNPs (Fig. 1A). The absence of Ro60 and La from A3F RNPs was clear (Fig. 1), and this correlated with the lack of Y RNAs in these complexes (Fig. 3A). However, Alu RNA was present in A3F RNPs (Fig. 3A), and robust inhibition of Alu retrotransposition was demonstrated (Fig. 3C), consistent with the notion that APOBEC protein-containing RNPs serve to protect against retrotransposition. Finally, given the strong evolutionary selection pressures that have been exerted on the APOBEC proteins (52) and the functional differences outlined above, it is perhaps to be expected that differences between A3F and A3G RNPs would be found. A key question is, therefore: what evolutionary forces have selected for such differences? Defining the RNAs and proteins that interact with each APOBEC protein as well as determining the patterns of inhibition of exogenous viruses and endogenous parasitic elements will help to address this issue.


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ACKNOWLEDGMENTS
 
We thank Hal Bogerd, Jez Carlton, Bryan Cullen, Thierry Heidmann, Juan Martin-Serrano, and John Moran for reagents.

This work was supported by the U. K. Medical Research Council and the Biotechnology and Biological Sciences Research Council. S.G.-M. is a Fellow of the European Molecular Biology Organization, C.M.S. is a Research Councils U. K. Academic Fellow, and M.H.M. is an Elizabeth Glaser Scientist.


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FOOTNOTES
 
* Corresponding author. Mailing address: Department of Infectious Diseases, King's College London School of Medicine, 2nd Floor, Borough Wing, Guy's Hospital, London Bridge, London SE1 9RT, United Kingdom. Phone: (44) 20 718 80149. Fax: (44) 20 718 80147. E-mail: michael.malim{at}kcl.ac.uk Back

{triangledown} Published ahead of print on 26 March 2008. Back


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Journal of Virology, June 2008, p. 5636-5642, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.00287-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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