Nucleocytoplasmic transport: integrating mRNA production and turnover with export through the nuclear pore.

Abstract

Separation of the nucleus and cytoplasm, maintained by two membrane bilayers that form the nuclear envelope, allows for spatial control over transcription factors and signaling molecules. This compartmentalization further ensures the presence of specialized environments for different stages of gene expression, such as transcription and protein production. Selective exchange between these two compartments is clearly important as well. Whereas many types of active transport between the nucleus and cytoplasm rely on transport receptors in the importin-β superfamily, export of mRNA utilizes distinct soluble machinery (6, 92). Moreover, in general mRNA export does not depend on a specific motif in the cargo, as has been demonstrated in many other cases of receptor-cargo interactions (22). Recent progress in identifying soluble factors important to mRNA trafficking is beginning to reveal the molecular basis for functional coupling between steps in mRNA biogenesis and how such coupling, rather than a consensus motif, brings specificity to mRNA export. Studies with Saccharomyces cerevisiae revealed that the key modulators of cellular mRNA export are unrelated to canonical importin-β-related receptors. Specifically, yeast deficient in a gene called MEX67 accumulate poly(A)+ RNA in the nucleus (73). A second protein, Mtr2p, binds Mex67p, and this interaction is required for the export of poly(A)+ RNA in yeast (71, 77). In an independent avenue of investigation, involving metazoan cells and the simian type D retrovirus Mason Pfizer monkey virus, the cellular protein TAP was found to facilitate export of RNA containing the viral constitutive transport element (CTE) (8, 32). TAP, confirmed to be the human orthologue of Mex67p, has been redesignated NXF1 (nuclear export factor 1). NXF1 interacts with p15/NXT1, the presumed functional homologue of Mtr2p (33, 44). Although Mtr2p and p15 share no sequence similarity, the Mex67p-Mtr2p complex displays similar structural architecture to the NXF1-p15 heterodimer (21). Indeed, the mRNA export defect in yeast cells deficient in both Mex67p and Mtr2p can be rescued by expression of human NXF1 and its cofactor p15 (44). Expression knock-down studies using RNA interference have demonstrated that NXF1 and p15 are required for poly(A)+ RNA export (35, 84, 93), further strengthening the case for an evolutionarily conserved system of mRNA export that is distinct from the importin-β superfamily. Likewise, studies with Xenopus oocytes support the conclusion that the small GTPase Ran, a key modulator of importin-β-type receptors, is not key to mRNA export (10). However, the distinction between mRNA export and the importin-β family/Ran network is not absolute, as an importin-β family member has recently been implicated in mRNA export as well (74).