Viral Regulation of mRNA Export

Abstract

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 5Ј end, cleavage and polyadenylation to form the 3Ј 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) ϩ 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) ϩ RNA, indicating a direct role in mRNA export. 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) ( (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 pr...

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Murine Leukemia Virus Uses NXF1 for Nuclear Export of Spliced and Unspliced Viral Transcripts

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