Nuclear–Cytoplasmic Transport

Abstract

In eukaryotic cells, the genomic DNA in the nucleus is separated from the translational machinery in the cytoplasm by the nuclear envelope. Transport of macromolecules such as proteins and RNA across this membrane is essential for cellular function and requires active nuclear–cytoplasmic transport systems. These systems consist of soluble transport receptors, which recognise and bind cargo in one compartment, mediate transport through nuclear pore complexes embedded in the nuclear envelope and deliver cargo in the target compartment. Disruption of this highly regulated process results in abnormal cell function and is linked to human disease aetiology. Understanding the contribution of nuclear protein and RNA transport to cellular organisation is one of the major challenges in cell biology.

Key Concepts

  • Transport into and out of the nucleus is mediated by nuclear pore complexes (NPCs), which are large proteinaceous channels that perforate the nuclear membrane.
  • Proteins destined for import into the nucleus contain a nuclear localisation signal (NLS) and proteins destined for export from the nucleus contain a nuclear export signal (NES), each of which targets them for transport.
  • Soluble transport receptors called importins and exportins or karyopherins recognise and bind macromolecular cargos and facilitate transport through nuclear pore complexes.
  • The asymmetric distribution of RanGDP in the cytoplasm and RanGTP in the nucleus controls the directionality of nuclear transport.
  • Nuclear protein transport can be regulated through inter‐ or intramolecular occlusion of the NLS or NES, post‐translation modification of the targeting signal, compartmental sequestration of the cargo protein or altering properties of the nuclear transport machinery including receptors and nuclear pores.
  • Many classes of RNA are transported via Ran‐regulated, karyopherin‐dependent pathways.
  • mRNA export is highly coupled to mRNA processing and is mediated by distinct receptors.
  • Mutations in nuclear targeting signals and nuclear transport receptors have been linked to several human diseases.

Keywords: nuclear transport; importin; karyopherin; nuclear pore complex; nucleocytoplasmic trafficking

Figure 1. The nuclear pore complex. Cartoon representation of a cross section of the nuclear pore, which is composed of a cylindrical channel embedded in the nuclear membrane, filaments extending into the cytoplasm and a basket structure reaching into the nucleus (Alber ., ).
Figure 2. Vertebrate and nucleoporins. The nucleoporin proteins or Nups that make up the nuclear pore are highly conserved. This schematic provides the names of budding yeast proteins (indicated on the right) and the corresponding vertebrate proteins (indicated on the left) of the nuclear pore. The cytoplasmic side is at the top (in red) and the nuclear basket is at the bottom (in light blue). Nups in green are intermembrane proteins. Nups in orange make up the central channel. Adapted from Bonnet and Palancade (2014).
Figure 3. The Ran gradient. The proteins that regulate the Ran cycle are asymmetrically distributed in the cell, with the Ran GTPase activating protein (RanGAP) in the cytoplasm and the Ran guanine nucleotide exchange factor (RanGEF) in the nucleus (Bischoff and Ponstingl, ). This distribution results in a predominantly cytoplasmic localisation for RanGDP and a predominantly nuclear localisation for RanGTP. Reproduced from Kalab et al. (2002) PubMed (http://www.ncbi.nlm.nih.gov/pubmed/).
Figure 4. The classical nuclear import cycle. In the cytoplasm, cargo containing an NLS is bound by the heterodimeric import receptor, importin α/importin β. Importin α recognises the NLS and importin β mediates interactions with the nuclear pore during translocation. Once inside the nucleus, RanGTP binding causes a conformational change in importin β, which releases the IBB region of importin α. This auto‐inhibitory domain, together with Nup2 and Cse1, facilitates NLS dissociation and delivery of the NLS cargo in the nucleus (Gilchrist ., ). Finally, importin α is recycled back to the cytoplasm by the export receptor, Cse1, in complex with RanGTP.
Figure 5. Karyopherin crystal structures. (a) Importin α lacking the IBB domain bound to two SV40 NLS peptides (Protein Data Bank entry 1BK6) (Conti ., ). Importin α (amino acids 88–530) is shown in . The SV40 peptides are shown in . (b) The classical β‐karyopherin, importin β, bound to two different binding partners. Importin β is shown in and the binding partner is shown in . On the left, importin β is bound on a convex face by the FG repeats of the nucleoporin, Nup1. On the right, importin β is bound on a concave surface by the NLS of parathyroid hormone‐related protein, PTHrP. (Protein Data Bank entries 2BPT and 1M5N) (Cingolani ., ; Liu and Stewart, ).
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Tran EJ, King MC and Corbett AH (2014b) Macromolecular transport between the nucleus and the cytoplasm: advances in mechanism and emerging links to disease. Biochimica et Biophysica Acta 1843: 2784–2795.

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McPherson, Annie J, Lange, Allison, Doetsch, Paul W, and Corbett, Anita H(Mar 2015) Nuclear–Cytoplasmic Transport. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001351.pub3]