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Journal of Virology, May 2004, p. 4389-4396, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4389-4396.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

MINIREVIEW

Viral Regulation of mRNA Export

Rozanne M. Sandri-Goldin*

Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697-4025


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INTRODUCTION
 
Recent advances have led to an understanding of how eukaryotic mRNAs are exported from the nucleus to the cytoplasm. This process involves an elaborate machinery that is conserved from yeasts to humans and is coupled to upstream events in RNA metabolism. Eukaryotic pre-mRNAs are processed after synthesis in the nucleus by capping at the 5' end, cleavage and polyadenylation to form the 3' end, and splicing to remove intervening sequences. Following processing, mRNAs must be exported through the nuclear pore complex (NPC) to the cytoplasm for translation, which requires recognition by export factors to direct the mRNAs to nuclear export receptors for translocation through the NPC (17, 81, 108). A large body of evidence shows that TAP/NXF1, in conjunction with its heterodimeric partner, p15/NXT, is the nuclear export receptor for mRNAs in metazoans (5, 27, 33, 45, 48, 107) (Table 1). The yeast homologue of TAP/NXF1, termed Mex67p, has been shown to function as the mRNA export receptor in yeasts (44, 88, 91, 101). TAP/NXF1 and Mex67p have been shown to shuttle between the nucleus and cytoplasm, cross-link to poly(A)+ RNA, localize at the nuclear pores, and interact directly with nucleoporins (5, 37, 45, 88, 91). Further, overexpression of TAP/NXF1 in Xenopus oocytes or mammalian cells stimulated mRNA export (5, 37), and inactivation of TAP/NXF1 in Caenorhabditis elegans (103) and Drosophila (38) by RNA interference blocked nuclear export of poly(A)+ RNA, indicating a direct role in mRNA export.


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  		TABLE 1. Glossary of mRNA export factors

In metazoans, nuclear export of mRNAs has also been linked to pre-mRNA splicing. Early reports showed that certain mRNAs transcribed from cDNAs failed to exit the nucleus and, therefore, did not express protein, whereas the same mRNAs expressed from intron-containing constructs could enter the cytoplasm and be efficiently translated (78, 85). Recently, it was reported that spliced RNAs were more efficiently exported from Xenopus oocyte nuclei than identical RNAs transcribed from cDNAs (65). The basis of this connection was uncovered in 2000 with the discovery of a protein complex that is deposited on pre-mRNAs undergoing splicing at a specific position about 20 nucleotides upstream of exon junctions (54-56). This exon junction complex (EJC) consists of at least six proteins, which have been shown to function in splicing, nuclear export, RNA localization, and mRNA surveillance (57, 81, 105) (Table 1). One of these proteins, termed Aly/REF (Table 1), the metazoan homologue of the yeast export factor Yra1p (99, 109), interacts directly with TAP/NXF1 (102) and is recruited to pre-mRNA sites near exon junctions (54, 55) by a DEAD-box helicase termed UAP56, which functions in spliceosome assembly (66) and also appears to have a role in mRNA export beyond the recruitment of Aly/REF (29). A role for Aly/REF in export of metazoan mRNAs is supported by the observations that Aly/REF remains tightly bound to the spliced mRNA (81, 110), that antibodies to Aly/REF that prevent its interaction with RNA reduced export of mRNA after microinjection in Xenopus oocytes (82), and that excess Aly/REF increased the rate and efficiency of mRNA export in vivo (82, 110). Thus, one or more proteins in the EJC appear to mark the mRNA for export through the TAP/NXF1 pathway (15).

However, it should be noted that, although splicing can enhance RNA export from intron-containing genes, it is not an absolute requirement because export factors can interact with RNA independently of splicing (81, 82). Furthermore, naturally intronless transcripts (e.g., histones) contain specific sequences that recruit export factors independently of splicing (43). In yeasts, where fewer than 5% of genes encode introns, recruitment of export proteins has been shown to occur cotranscriptionally (58). Interestingly, though, Yra1, the yeast Aly/REF homologue, associates with introns of intron-containing genes in a splicing-dependent manner, whereas Yra1 recruitment to genes without introns is not dependent on splicing (59). A model put forward by Reed and Magni (80) to explain the apparent link between splicing and export in metazoan cells is based on the fact that, in metazoans, introns are abundant and are typically thousands to tens of thousands of nucleotides in length. In contrast, exons are small, averaging from 100 to 300 nucleotides. Thus, marking exon junctions by the binding of export factors assures that mRNA will be exported and that the vast preponderance of intronic RNA will be retained in the nucleus. This creates an interesting paradox for nuclear replicating viruses, which require efficient export of their transcripts but which express genes whose expressed mRNAs are unspliced or intronless. The former include the simple retroviruses and lentiviruses, which encode essential proteins in RNAs that are partly spliced or unspliced. The latter group is characterized by the herpesviruses, several members of which encode predominately intronless transcripts. The factors that these viruses encode and the mechanisms that they have evolved to circumvent retention or inefficient export of unspliced or intronless mRNAs will be the topic of this review.


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EXPORT OF UNSPLICED RETROVIRAL RNA
 
Although retroviruses are RNA viruses, they replicate their genomic RNA through a proviral DNA intermediate that is initially synthesized by reverse transcriptase. The provirus, which is integrated in the host genome, is transcribed by RNA polymerase II and undergoes processing, including splicing, like that of any other metazoan pre-mRNA. However, retroviruses must express fully spliced, singly spliced, and unspliced versions of the same initial transcript in the cytoplasm of the infected cell (14). There, unspliced RNAs serve both as transcripts for the translation of essential retroviral proteins and as genomic RNAs that are packaged into assembling virions (9). However, splicing is not only involved in marking spliced mRNAs for export through the EJC, but the splicing machinery is also involved in the retention of unspliced transcripts in the nucleus. Nuclear retention is caused by interactions of splicing factors with splice site consensus sequences in partially processed transcripts (53) and serves to ensure that translation occurs only on mature mRNAs. Retroviruses have evolved mechanisms to circumvent this nuclear retention and allow export of unspliced RNAs.


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HIV-1 Rev AND CRM1
 
The first RNA export pathway to be elucidated was the CRM1 pathway, which is utilized by human immunodeficiency virus (HIV) through the mediation of the Rev protein (Table 1). HIV type 1 (HIV-1) is a complex retrovirus or lentivirus, which has a total of nine genes that are expressed by alternative splicing of a single genome-length proviral transcript that also forms the RNA genome (13). HIV-1 replication requires the nuclear export and translation of unspliced, singly spliced, and multiply spliced derivatives of the proviral transcript. Fully spliced mRNAs encode viral regulatory proteins; incompletely spliced mRNAs encode viral structural proteins, and unspliced RNA serves as genomic RNA and is packaged into virions (9, 104). Early studies showed that the Rev protein was absolutely required for expression of viral structural proteins encoded by incompletely spliced viral mRNAs (93). Later, it was demonstrated that these viral mRNAs were expressed but were unable to reach the cytoplasm in the absence of Rev (19, 22). Nuclear export of these mRNAs depended upon the binding of multiple copies of Rev to a cis-acting, highly structured RNA target termed the Rev response element (RRE) (24, 68, 69). An N-terminal arginine-rich sequence serves as both a nuclear localization signal (NLS) and the RRE-specific RNA binding domain, and this motif is flanked by sequences that mediate the multimerization of Rev on the RRE (68) (Fig. 1). A critical leucine-rich motif, initially termed the Rev activation domain, was also found to be essential for Rev function (67). An important development in unraveling Rev function was the demonstration that this leucine-rich sequence served as a nuclear export signal (NES) (23). NES sequences of the leucine-rich type were subsequently shown to bind CRM1, a nuclear export factor belonging to the importin/exportin or karyopherin family of nuclear transport receptors (26, 98) (Fig. 1). Nucleocytoplasmic transport mediated by the importin/exportin family is energy dependent and requires the small GTPase Ran and components of the Ran GTPase system, including the GTPase-activating protein, RanGAP1, and the Ran binding protein, RanBP1. The asymmetric distribution of these factors in the cell results in a RanGTP:RanGDP gradient in which the RanGTP concentration is high in the nucleus (reviewed in reference 26). Nuclear export of bound HIV-1 mRNAs is dependent on the interaction between Rev and CRM1 and requires CRM1 association with RanGTP (reviewed in reference 16) (Fig. 1).



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  		FIG. 1. HIV Rev exports unspliced viral mRNAs through the CRM1 export receptor. CRM1 is a member of the importin/exportin or karyopherin family of nuclear transport receptors (26, 70). Nucleocytoplasmic transport mediated by the importin/exportin family requires the small GTPase Ran. RanGTP concentrations are high in the nucleus, while RanGDP concentrations are high in the cytoplasm. Import of cargo requires binding to an importin. After translocation through the NPC, RanGTP in the nucleus dissociates the cargo from importin, which binds RanGTP to be recycled to the cytoplasm. Export from the nucleus requires binding of the cargo to a nuclear exportin, which binds RanGTP in a trimeric complex. In the cytoplasm, the Ran GTPase, RanGAP, converts RanGTP to RanGDP, resulting in the release of the cargo and the exportin (reviewed in reference 17). Rev binds to the highly structured RRE in unspliced HIV mRNA and interacts with CRM1 through its leucine-rich NES. This interaction can be blocked by LMB. CRM1 binds RanGTP and Rev, which is bound to the cargo RNA for translocation through the NPC.

The CRM1 pathway is also used by other complex retroviruses. These include the Rev proteins of all members of the lentivirus family and the human T-cell leukemia virus, which encodes a protein termed Rex (35). A specific inhibitor of CRM1, the drug leptomycin B (LMB), allows the identification of proteins and RNAs that depend upon CRM1 for export to the cytoplasm. LMB covalently modifies CRM1 at a conserved residue that is required for binding by leucine-rich NESs (51, 52). Studies employing LMB inhibition have demonstrated that CRM1 is a major pathway for export of cellular proteins and snRNAs but that only a small number of mRNAs utilize the CRM1 pathway (reviewed in reference 17).


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SIMPLE RETROVIRUSES AND THE CTE
 
Unlike lentiviruses, simple retroviruses do not encode trans-acting factors like Rev, yet these viruses also require the export of partly spliced and unspliced transcripts. It is ironic that studies to uncover how these RNAs are exported led to the discovery of the major cellular mRNA export pathway. Studies with Mason-Pfizer monkey virus identified a highly structured cis-acting RNA element that was sufficient for nuclear export of incompletely spliced viral mRNAs (20). This element was termed the constitutive transport element (CTE) (Table 1). TAP, later also termed NXF1 (nuclear export factor 1), was first identified as the cellular cofactor interacting with the CTE in type D retrovirus RNAs, and TAP/NXF1 was shown to promote the export of CTE-containing transcripts (1, 33, 45) (Fig. 2). That TAP/NXF1 was involved in cellular mRNA export was first demonstrated by nuclear injection of excess CTE into Xenopus oocytes, which competed with the export of cellular mRNAs but not of snRNAs, which use the CRM1 pathway (86). Unlike cellular mRNAs, which bind to TAP/NXF1 through export adaptor proteins such as Aly/REF, the CTE binds directly to TAP/NXF1. The N-terminal region of the 619-amino-acid hTAP/NXF1 protein is required for binding to the CTE and spans a noncanonical RNP-like RNA binding domain and four leucine-rich repeats (1, 6). The central domain of TAP/NXF1 interacts with p15/NXT1, and complex formation between TAP/NXF1 and p15/NXT1 affects its binding to FG-repeat nucleoporins and enhances its shuttling activity (48). TAP/NXF1 interacts directly with the FG-nucleoporins in the NPC through its C terminus, and thus, unlike CRM1, binding to RanGTP is not required for TAP/NXF1 export activity (89, 107, 108) (Fig. 2).



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  		FIG. 2. Unspliced mRNA encoded by simple retroviruses and intronless mRNAs encoded by HSV-1 use the cellular TAP/NXF1 nuclear export receptor. In Mason-Pfizer monkey virus, the CTE, a structured element present in the unspliced mRNA, binds directly to TAP/NXF1/p15, the export receptor that is used by cellular mRNAs (86). During splicing of metazoan pre-mRNA, a complex of proteins termed the EJC is deposited on the spliced RNA at a position just upstream of exon junctions. Aly/REF, one of the components of this complex, is recruited to exon junctions by UAP56, which appears to have roles in splicing and export. Aly/REF remains bound to the spliced RNA and directs it to TAP/NXF1, with which it interacts directly (for review see reference 79). In HSV-1-infected cells, ICP27 inhibits host cell splicing by interacting with SR splicing factors and an SR-specific kinase, SRPK1, which results in inappropriate phosphorylation of SR proteins. Splicing complex formation is stalled before the first catalytic step (90), and incompletely spliced RNAs are retained in stalled spliceosomal complexes. ICP27 interacts with Aly/REF and recruits it to sites of HSV-1 transcription. ICP27 binds viral mRNAs, and the ICP27-Aly/REF-RNA complex is directed to TAP/NXF1 (10, 49).


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HERPESVIRUSES AND THE EXPORT OF INTRONLESS mRNAs
 
Herpes simplex virus type 1 (HSV-1) is a human alphaherpesvirus that expresses more than 80 transcripts during viral lytic infection. The unusual feature of HSV-1 transcripts is that the majority are intronless and thus do not interact with the splicing machinery. For this reason, nuclear retention of intron-containing mRNAs is not a problem for HSV-1, yet a lack of splicing still affects the efficiency of export of mRNAs because most HSV-1 mRNAs do not interact with splicing complexes and therefore do not acquire EJCs. Splicing is not an absolute requirement for export because there are a number of cellular intronless transcripts, for example, histones. However, these RNAs often contain specific sequences that recruit export factors independently of splicing (41-43). One such signal was reported in the HSV-1 thymidine kinase mRNA, and it was shown that hnRNP L bound to this sequence (63). No other role for hnRNP L in RNA export has been established.


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THE ROLE OF ICP27 IN SPLICING AND EXPORT
 
Like HIV-1, HSV-1 encodes a trans-acting protein that is involved in the export of viral mRNAs. This factor, termed ICP27, is a 512-amino-acid protein that shuttles between the nucleus and cytoplasm at later times during infection (72, 77, 87, 95). ICP27 has been found to bind several intronless viral RNAs in vivo, and an N-terminal RGG box RNA binding motif is required for this binding (71, 87). In addition, three C-terminal domains display homology to KH RNA binding motifs and could also be involved in RNA binding affinity and specificity (97). Although a specific viral RNA binding sequence has not yet been identified, HSV-1 RNAs that map to 28 open reading frames were recently identified as interacting with preferred specificity for ICP27 in a yeast three-hybrid screen (94). However, the activity of ICP27 in RNA export is more complex than RNA binding and shuttling. Early in infection, host cell splicing is inhibited by the action of ICP27 (7, 36, 61). This not only prevents the complete processing of cellular pre-mRNAs but ensures that these incompletely spliced transcripts will be retained in the nucleus in stalled spliceosomal complexes. ICP27 inhibits host cell splicing by recruiting a predominantly cytoplasmic kinase, termed SR protein kinase 1 (SRPK1), to the nucleus (90). The interaction of ICP27 with SRPK1 alters its ability to phosphorylate members of an essential family of splicing factors, called SR proteins, that play important roles in spliceosome assembly (90). The result is that splicing complex formation is stalled before the first catalytic step (7, 61, 90) (Fig. 2).

ICP27 interacts with SR proteins (90) and with other spliceosomal components (7), including the RNA export adaptor Aly/REF (10, 49), which is part of the EJC. Aly/REF interacts with TAP/NXF1 directly (110). The interaction of ICP27 with Aly/REF, first demonstrated in yeast two-hybrid screens (10, 49), was also shown to occur in virus-infected cells and was found to be independent of RNA bridging by in vitro binding assays (10, 49). The region of ICP27 required for Aly/REF interaction overlaps the NLS and is adjacent to the RGG motif. Thus, the region from amino acids 104 to 138 appears to be important for both import of ICP27 to the nucleus and export of ICP27-bound viral RNAs to the cytoplasm. Overexpression of Aly/REF in HSV-1-infected cells increased the export efficiency of several late mRNAs (10), supporting a role for Aly/REF in HSV-1 RNA export. Further, in experiments in which microinjection of intronless viral mRNAs into Xenopus oocytes was used, export was dramatically stimulated by ICP27, whereas a mutant that does not interact with Aly/REF was inactive in RNA export (49). In virus-infected cells, Aly/REF, which normally colocalizes with splicing proteins (110), instead colocalized with ICP27 and moved to regions that resembled HSV-1 transcription/replication complexes (10). These were shown to be viral sites of transcription by costaining with an antibody to an HSV-1 transcription factor (L. Li and R. M. Sandri-Goldin, unpublished results). Furthermore, a viral mutant with a deletion within the Aly/REF interaction region failed to recruit Aly/REF to sites of viral transcription, and instead Aly/REF colocalized with splicing factors (Li and Sandri-Goldin, unpublished). Thus, ICP27 appears to recruit Aly/REF from cellular splicing complexes to sites of HSV-1 transcription (Fig. 2). Recent reports for which small interfering RNA (siRNA) strategies were used to knock down levels of Aly/REF in Drosophila (29) and C. elegans (64) have demonstrated that Aly/REF and other EJC components may be dispensable for mRNA export in these organisms, unlike the situation in yeast, where the Aly/REF homologue Yra1 is required for mRNA export (99). At least one ICP27 mutant that fails to recruit Aly/REF to transcription sites is defective in viral RNA export (Li and Sandri-Goldin, unpublished). However, it is certainly possible that other adaptor proteins are also involved in HSV-1 RNA export.

ICP27 was also shown to interact with TAP/NXF1 in HSV-1-infected cells (10, 49). The region of ICP27 required for this interaction resides in the C terminus (I. B. Chen and Sandri-Goldin, unpublished results). That ICP27 directs viral intronless RNAs to the TAP/NXF1 pathway was unexpected. ICP27 encodes an N-terminal leucine-rich sequence that can function as an NES when fused to a heterologous protein, and deletion or mutation of this region decreases ICP27 export to the cytoplasm (10, 87). Further, ICP27 shuttling was reported to be sensitive to the CRM1 inhibitor LMB (75, 96). However, in microinjection studies with Xenopus oocytes, neither ICP27 shuttling nor export of viral RNA was sensitive to LMB (49). Furthermore, in HSV-1-infected cells export of ICP27 to the cytoplasm was not affected by LMB (10). In contrast, export of viral mRNAs by ICP27 in oocytes was blocked by coinjecting an excess of CTE to saturate TAP/NXF1 (49), and expression of a trans-dominant negative mutant of TAP/NXF1, which lacks the C-terminal nucleoporin interaction domain, retained ICP27 in the nucleus of infected cells (10). Thus, ICP27 was unable to exit the nucleus if TAP/NXF1 was blocked. Further, ICP27 was not found to interact with CRM1 in yeast or in infected cells (10). The role of the N-terminal leucine-rich region of ICP27 is unclear. Interestingly, replacement of this sequence with the authentic NES from HIV Rev still rendered ICP27 insensitive to LMB, even though the Rev NES is known to interact with CRM1 (10). It is possible that this N-terminal region is normally masked by protein folding in the native ICP27 molecule. Disruption by mutation (60, 87) may affect ICP27 secondary structure, and that may account for the effects observed on export. It should also be noted that it was reported that some HSV-1 RNAs were exported in the presence of LMB, whereas export of others appeared to be CRM1 dependent (96). Therefore, it is possible that some HSV-1 RNAs can be exported independently of ICP27 and that other export factors may play a role. This is an area that requires further investigation.


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ICP27 HOMOLOGUES IN HUMAN HERPESVIRUSES
 
trans-Acting proteins that share homology with ICP27 have also been implicated in RNA export in other human herpesviruses. During lytic infection of a human gammaherpesvirus, Epstein-Barr virus (EBV), most early and late mRNAs are transcribed from intronless genes. The EBV homologue of ICP27, a protein that is called SM and is also called EB2, Mta and BMLF1, has been shown to shuttle between the nucleus and cytoplasm (4, 8, 11). Further, SM has been reported to inhibit expression of intron-containing genes (84), which suggested a role in splicing inhibition similar to that of ICP27. However, another study showed that SM inhibited accumulation of unspliced RNAs only when these RNAs were poor splicing substrates and that there was no effect on spliced RNAs (21). It should be noted that in both studies the RNAs were generated from transfected reporter constructs. Although colocalization studies showed that SM associates with splicing factors (92), effects on host cell splicing were not investigated directly. Therefore, it is not clear whether SM has an effect on cellular splicing. SM has been shown to increase the cytoplasmic accumulation of intronless RNAs, including those of the EBV replication genes (21, 92). Further, SM was shown to bind specific RNAs in vitro (8, 92) and in vivo (83), though a specific RNA binding recognition sequence has not been identified. Recently, the RNA binding domain of SM was defined and was shown to be an arginine-rich region similar to arginine-rich RNA binding motifs found in a number of RNA binding proteins (39). This region is not homologous to the RGG box of ICP27.

There are conflicting reports on whether SM export occurs through the CRM1 or TAP/NXF1 pathway. Two leucine-rich sequences were identified as putative NESs (11), and deletion of both motifs eliminated shuttling, suggesting that SM may have two NESs (11). Subsequently, it was reported that SM interacts with CRM1 in vivo, and in reporter assays SM-mediated export of intronless RNAs was sensitive to LMB (4). In contrast, studies by another group demonstrated that SM exports unspliced RNA via a CRM1-independent pathway and that SM export was unaffected by LMB (21). Later this same group showed that the leucine-rich double NES was actually an interaction domain for Aly/REF (40). Further, SM was found in RNase-sensitive complexes in vivo that contained both Aly/REF and TAP/NXF1. An N-terminal region was defined as a novel, transferable NES that is CRM1 independent (40). Therefore, defects in export activity that arose through mutation of the two leucine-rich regions in earlier studies may have resulted from the inability of SM to interact with Aly/REF.

Interestingly, SM and ICP27 share little homology in the Aly/REF interaction domain, the RNA binding domain, or other N-terminal regions. The most highly conserved residues between the two proteins occur in the C terminus (12). Both ICP27 and SM are essential virus proteins. ICP27 was unable to complement an SM deletion mutant (32), and SM only weakly complemented an ICP27-null mutant (3), suggesting that each has evolved functions that are specific for the life cycle of their respective viruses within the host cell. Another homologue, UL69, encoded by the betaherpesvirus cytomegalovirus, is even more distantly related to ICP27 (12). UL69 has also been reported to shuttle, and a novel LMB-insensitive nuclear export sequence was identified (62). It has not been determined whether UL69 has a role in the export of cytomegalovirus mRNAs.


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SPLICING AND EXPORT IN ADENOVIRUS
 
The adenovirus protein E1B 55-kDA interacts with the E4 Orf6 protein to induce selective export of viral late RNAs to the cytoplasm, while retaining cellular RNAs in the nucleus (25). There is a temporal shift that occurs in splicing in adenovirus-infected cells in that cellular splicing is inhibited and splicing shifts to viral late transcripts. This shift has been shown to occur because another viral protein, E4 Orf4, activates dephosphorylation of the essential SR splicing factor, ASF/SF2, which plays a role in splice site selection, and because splicing of adenovirus late pre-mRNAs becomes favored (76). The dephosphorylation occurs because E4 Orf4 activates protein phosphatase 2 (46, 47, 74, 76). This is presumably the reason that cellular transcripts are retained in the nucleus late in adenovirus infection. The role of the E1B 55-kDa and E4 Orf6 complex in export has been less well defined mechanistically. Initially, a Rev-like NES was uncovered in E4 Orf6 and it was proposed that the E1B 55-kDa and E4 Orf6 complex functions to export viral RNAs and that E4 Orf6 directed both import and export of the complex (18). More recently, E1B 55-kDa was shown to shuttle on its own in a CRM1-dependent manner (50). Mutation of the NES within E4 Orf6 or mutations in E1B 55-kDa impaired late RNA accumulation in the cytoplasm and resulted in reductions in virus yields (31, 106). However, in the case of E1B 55-kDa, the mutant viruses expressed low levels of E1B 55-kDa (31). Therefore, the specific roles of E1B 55-kDa and E4 Orf6 in adenovirus RNA export have not been elucidated beyond their ability to shuttle between the nucleus and cytoplasm.


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PERSPECTIVES
 
It is now clear that nuclear replicating viruses have evolved clever and intricate mechanisms to ensure that their transcripts will be expressed and that viral progeny will be produced. The mechanisms range from the evolution of a structured RNA element in the simple retroviruses, which can bind directly to the cellular mRNA export receptor, to the hijacking of cellular mRNA export adaptors, while at the same time inhibiting cellular RNA processing and export, as seen with HSV-1. In contrast, HIV uses an export receptor that is predominantly utilized by protein and snRNAs. Unraveling these mechanisms has not only provided insight into virus-host interactions and pointed to novel antiviral targets but has also helped to elucidate the cellular export pathways.


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FOOTNOTES
 
* Mailing address: Department of Microbiology and Molecular Genetics, College of Medicine, Medical Sciences I, B240, University of California, Irvine, CA 92697-4025. Phone: (949) 824-7570. Fax: (949) 824-9054. E-mail: rmsandri{at}uci.edu. Back


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Journal of Virology, May 2004, p. 4389-4396, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4389-4396.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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