Exportin 4: a mediator of a novel nuclear export pathway in higher eukaryotes

Abstract

Transport receptors of the importin β superfamily account for many of the nuclear import and export events in eukaryotic cells. They mediate translocation through nuclear pore complexes, shuttle between nucleus and cytoplasm and co‐operate with the RanGTPase system to regulate their interactions with cargo molecules in a compartment‐specific manner. We used affinity chromatography on immobilized RanGTP to isolate further candidate nuclear transport receptors and thereby identified exportin 4 as the most distant member of the importin β family so far. Exportin 4 appears to be conserved amongst higher eukaryotes, but lacks obvious orthologues in yeast. It mediates nuclear export of eIF‐5A (eukaryotic translation initiation factor 5A) and possibly that of other cargoes. The export signal in eIF‐5A appears to be complex and to involve the hypusine modification that is unique to eIF‐5A. We discuss possible cellular roles for nuclear export of eIF‐5A.

Karyopherin β2B participates in mRNA export from the nucleus

“…Approximately 22 structurally related Kap ␤ proteins occur in mammalian cells, but only 14 in Saccharomyces cerevisiae (6-10), indicating that some nucleocytoplasmic transport pathways exist in higher eukaryotes but not in yeast. Among the Kaps shown to function in export, exportin-4 lacks also an obvious yeast orthologue (45). A possible explanation for the difference in mRNA export between yeast and higher eukaryotes is that the export rate allowed by direct interaction of TAP with nucleoporins is sufficient in yeast, but not in higher eukaryotes.…”

“…RanGAP1 stimulates the GTPase activity of Ran (43), and binding of Kaps to RanGTP strongly reduces the stimulation by RanGAP1. The dissociation constants of the complexes formed by the Kaps with RanGTP can be estimated from the dose dependence of this effect (44)(45)(46)(47). This assay revealed that the Kap ␤2B͞RanGTP complex has an apparent dissociation constant (K d ) of Ϸ300 nM, whereas the corresponding value for Kap ␤2A is Ϸ0.3 nM (Fig.…”

“…2). It is known that in the absence of their cargoes the nucleocytoplasmic export factors have high K d values for RanGTP, whereas the K d of import factors is in the low nanomolar range (44)(45)(46)(47). The K d of the Kap ␤2B͞RanGTP complex is in the range typical for export factors (Ͼ1 M for CRM1 and CAS, Ϸ1 M for exportin-t, and Ϸ40 nM for exportin-4).…”

Deoxyhypusine synthase haploinsufficiency attenuates acute cytokine signaling

“…For example, Hauber and colleagues 19 have observed that eIF5A binds and transports the HIV Rev protein from the nuclear to cytoplasmic compartment in conjunction with the nuclear protein exportin1/CRM1, yet other studies have disputed this particular function. 20,21 Nonetheless, our own studies in the context of inflammation in β cells suggest that a nuclear species of eIF5A binds and shuttles the mRNA encoding inducible nitric oxide synthase (iNOS) across the nuclear membrane in a manner dependent upon exportin1/CRM1. 22 We interpret this controversy as reflecting more the disparity of cell types and conditions that have been used to study eIF5A rather than actual functionality of the protein.…”

A New Crystal Structure of Deoxyhypusine Synthase Reveals the Configuration of the Active Enzyme and of an Enzyme·NAD·Inhibitor Ternary Complex

“…Specific inhibitors of DHS or deoxyhypusine hydroxylase result in cellular growth arrest and alter tumor cell proliferation and differentiation (5)(6)(7)(8)(9). Furthermore, the hypusine residue of eIF5A has been reported to be critical for in vitro RNA binding (10) and the interaction with exportin 4 (11).…”