Exportin 7 defines a novel general nuclear export pathway

ZMBH, INF 282, Heidelberg, Germany.
The EMBO Journal (Impact Factor: 10.43). 09/2004; 23(16):3227-36. DOI: 10.1038/sj.emboj.7600338
Source: PubMed


Most transport pathways between cell nucleus and cytoplasm are mediated by nuclear transport receptors of the importin beta family. These receptors are in continuous circulation between the two compartments and transfer cargo molecules from one side of the nuclear envelope to the other. RanBP16 is a family member from higher eukaryotes of so far unknown function. We now show that it exports p50RhoGAP from the nucleus and thereby confines this activity to the cytoplasm. It also accounts for nuclear exclusion of 14-3-3sigma, which in turn is known to anchor, for example, cyclin-dependent kinases in the cytoplasm. Our data further suggest that RanBP16 exports several additional cargoes. It thus appears to be a nuclear export mediator with broad substrate specificity and we will therefore refer to it as exportin 7 (Exp7). Finally, we demonstrate that Exp7-dependent nuclear export signals differ fundamentally from the leucine-rich, CRM1-dependent ones: First, they are not just short linear sequences, but instead include folded motifs. Second, basic residues are critical for Exp7 recruitment.

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Available from: José-Manuel Mingot, Oct 10, 2015
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    • "These receptors are called importins (Figure 1A) and those that export cargo out of the nucleus into the cytoplasm are called exportins (Figure 1C). Most of these receptors target a specific cargo to be transported, such as Impα for the cellular apoptosis susceptibility (CAS) protein (Kutay et al., 1997), tRNA for exportin-t (Arts et al., 1998; Kutay et al.,1998), actin-profilin complexes for exportin-6 (Stuven et al., 2003), and p50RhoGAP for exportin-7 (Mingot et al., 2004). Other receptors export a wide variety of cargoes out of nucleus such as Leurich nuclear export signal (NES) containing proteins by CRM1 (Fornerod et al., 1997; Stade et al., 1997), and dsRNA binding proteins, pre-miRNAs and 60S pre-ribosomal subunits by exportin-5 (Bohnsack et al., 2002; Calado et al., 2002; Gwizdek et al., 2003). "
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    DESCRIPTION: Review on nuclear transport with focus mainly on Exportin 6. Predicted structure and predicted mechanism of interaction.
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    • "There, substitution of the basic residues with alanines abolished NES activity in the protein context of hADI1 similar to our observations with PAPSS1. Basic residues contributing to nuclear export might be indicative for an involvement of exportin 7 in nuclear export [28], though the exact nuclear export signal for this export receptor has not been definitively established [29]. "
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    ABSTRACT: In higher eukaryotes, PAPS synthases are the only enzymes producing the essential sulphate-donor 3'-phospho-adenosine-5'-phosphosulphate (PAPS). Recently, PAPS synthases have been associated with several genetic diseases and retroviral infection. To improve our understanding of their pathobiological functions, we analysed the intracellular localisation of the two human PAPS synthases, PAPSS1 and PAPSS2. For both enzymes, we observed pronounced heterogeneity in their subcellular localisation. PAPSS1 was predominantly nuclear, whereas PAPSS2 localised mainly within the cytoplasm. Treatment with the nuclear export inhibitor leptomycin B had little effect on their localisation. However, a mutagenesis screen revealed an Arg-Arg motif at the kinase interface exhibiting export activity. Notably, both isoforms contain a conserved N-terminal basic Lys-Lys-Xaa-Lys motif indispensable for their nuclear localisation. This nuclear localisation signal was more efficient in PAPSS1 than in PAPSS2. The activities of the identified localisation signals were confirmed by microinjection studies. Collectively, we describe unusual localisation signals of both PAPS synthase isoforms, mobile enzymes capable of executing their function in the cytoplasm as well as in the nucleus.
    PLoS ONE 01/2012; 7(1):e29559. DOI:10.1371/journal.pone.0029559 · 3.23 Impact Factor
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    • "Exp-t (Xpot) Los1p/Kap127p tRNA Kutay et al (1998); Arts et al (1998a); Hellmuth et al (1998) Exportin 5 (Xpo5) tRNA, eEF1A (via aa-tRNA) Bohnsack et al (2002); Calado et al (2002) dsRNA-binding proteins (via dsRNA) Brownawell and Macara (2002) Pre-miRNAs Yi et al (2003); Bohnsack et al (2004); Lund et al (2004) 60S pre-ribosomal subunits Wild et al (2010) Exportin 6 Actin–profilin complexes Stü ven et al (2003) Exportin 7 p50RhoGAP, 14-3-3s Mingot et al (2004) "
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    ABSTRACT: Nuclear export is an essential eukaryotic activity. It proceeds through nuclear pore complexes (NPCs) and is mediated by soluble receptors that shuttle between nucleus and cytoplasm. RanGTPase-dependent export mediators (exportins) constitute the largest class of these carriers and are functionally highly versatile. All of these exportins load their substrates in response to RanGTP binding in the nucleus and traverse NPCs as ternary RanGTP-exportin-cargo complexes to the cytoplasm, where GTP hydrolysis leads to export complex disassembly. The different exportins vary greatly in their substrate range. Recent structural studies of both protein- and RNA-specific exporters have illuminated how exportins bind their cargoes, how Ran triggers cargo loading and how export complexes are disassembled in the cytoplasm. Here, we review the current state of knowledge and highlight emerging principles as well as prevailing questions.
    The EMBO Journal 08/2011; 30(17):3457-74. DOI:10.1038/emboj.2011.287 · 10.43 Impact Factor
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