Nuclear–Cytoplasmic Transport


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 et al., ).
Figure 2. Vertebrate and Saccharomyces cerevisiae 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 ().
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 (
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 et al., ). 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 et al., ). Importin α (amino acids 88–530) is shown in orange. The SV40 peptides are shown in yellow. (b) The classical β‐karyopherin, importin β, bound to two different binding partners. Importin β is shown in blue and the binding partner is shown in yellow. 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 et al., ; Liu and Stewart, ).


Aguilera A (2005) Cotranscriptional mRNP assembly: from the DNA to the nuclear pore. Current Opinion in Cell Biology 17 (3): 242–250.

Alber F, Dokudovskaya S, Veenhoff LM, et al. (2007) The molecular architecture of the nuclear pore complex. Nature 450 (7170): 695–701.

Bayliss R, Littlewood T and Stewart M (2000) Structural basis for the interaction between FxFG nucleoporin repeats and importin‐beta in nuclear trafficking. Cell 102: 99–108.

Beals CR, Clipstone NA, Ho SN and Crabtree GR (1997) Nuclear localization of NF‐ATc by a calcineurin‐dependent, cyclosporin‐sensitive intramolecular interaction. Genes & Development 11 (7): 824–834.

Bischoff FR and Ponstingl H (1991) Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1. Nature 354 (6348): 80–82.

Bonnet A and Palancade B (2014) Regulation of mRNA trafficking by nuclear pore complexes. Genes (Basel) 5 (3): 767–791.

Brinkmann U, Gallo M, Polymeropoulos MH and Pastan I (1996) The human CAS (cellular apoptosis susceptibility) gene mapping on chromosome 20q13 is amplified in BT474 breast cancer cells and part of aberrant chromosomes in breast and colon cancer cell lines. Genome Research 6: 187–194.

Cheung J and Smith DF (2000) Molecular chaperone interactions with steroid receptors: an update. Molecular Endocrinology 14: 939–946.

Cingolani G, Bednenko J, Gillespie MT and Gerace L (2002) Molecular basis for the recognition of a nonclassical nuclear localization signal by importin Beta. Molecular Cell 10 (6): 1345–1353.

Cingolani G, Petosa C, Weis K and Müller CW (1999) Structure of importin‐beta bound to the IBB domain of importin‐alpha. Nature 399: 221–229.

Conti E, Uy M, Leighton L, Blobel G and Kuriyan J (1998) Crystallographic analysis of the recognition of a nuclear localization signal by the nuclear import factor karyopherin alpha. Cell 94 (1998): 193–204.

Devos D, Dokudovskaya S, Williams R, et al. (2006) Simple fold composition and modular architecture of the nuclear pore complex. PNAS 103 (7): 2172–2177.

Fontes MR, Teh T, Jans D, Brinkworth RI and Kobe B (2003) Structural basis for the specificity of bipartite nuclear localization sequence binding by importin‐alpha. Journal of Biological Chemistry 278 (30): 27981–27987.

Fukuhara N, Fernandez E, Ebert J, Conti E and Svergun D (2004) Conformational variability of nucleo‐cytoplasmic transport factors. Journal of Biological Chemistry 279 (3): 2176–2181.

Gerace L and Burke B (1988) Functional organization of the nuclear envelope. Annual Review of Cell Biology 4: 335–374.

Gilchrist D, Mykytka B and Rexach M (2002) Accelerating the rate of disassembly of karyopherin‐cargo complexes. Journal of Biological Chemistry 277 (20): 18161–18172.

Goldfarb DS, Corbett AH, Mason DA, Harreman MT and Adam SA (2004) Importin alpha: a multipurpose nuclear‐transport receptor. Trends in Cell Biology 14 (9): 505–514.

Görlich D, Dabowski M, Bischoff FR, et al. (1997) A novel class of RanGTP binding proteins. Journal of Cell Biology 138: 65–80.

Gorlich D, Kostka S, Kraft R, et al. (1995) Two different subunits of importin cooperate to recognize nuclear localization signals and bind them to the nuclear envelope. Current Biology 5 (4): 383–392.

Gorsch LC, Dockendorff TC and Cole CN (1995) A conditional allele of the novel repeat‐containing yeast nucleoporin RAT7/NUP159 causes rapid cessation of mRNA export and reversible clustering of nuclear pore complexes. Journal of Cell Biology 129: 939–955.

Harreman MT, Cohen PE, Hodel MR, et al. (2003) Characterization of the auto‐inhibitory sequence within the N‐terminal domain of importin alpha. Journal of Biological Chemistry 278 (24): 21361–21369.

Hope TJ (1999) The ins and outs of HIV Rev. Archives of Biochemistry and Biophysics 365 (2): 186–191.

Huxford T, Huang DB, Malek S and Ghosh G (1998) The crystal structure of the IkappaBalpha/NF‐kappaB complex reveals mechanisms of NF‐kappaB inactivation. Cell 95 (6): 759–770.

Keeshan K, Cotter TG and McKenna SL (2003) Bcr‐Abl upregulates cytosolic p21WAF‐1/CIP‐1 by a phosphoinositide‐3‐kinase (PI3K)‐independent pathway. British Journal of Haematology 123 (1): 34–44.

Kim IS, Kim DH, Han SM, et al. (2000) Truncated form of importin alpha identified in breast cancer cell inhibits nuclear import of p53. Journal of Biological Chemistry 275 (30): 23139–23145.

Kobe B (1999) Autoinhibition by an internal nuclear localization signal revealed by the crystal structure of mammalian importin alpha. Nature Structural Biology 6: 301–304.

Lam DH and Aplan PD (2001) NUP98 gene fusions in hematologic malignancies. Leukemia 15 (11): 1689–1695.

Lee BJ, Cansizoglu AE, Suel KE, et al. (2006) Rules for nuclear localization sequence recognition by karyopherinbeta2. Cell 126 (3): 543–558.

Lee SJ, Sekimoto T, Yamashita E, et al. (2003) The structure of importin‐beta bound to SREBP‐2: nuclear import of a transcription factor. Science 302 (5650): 1571–1575.

Liu SM and Stewart MS (2005) Structural basis for the high‐affinity binding of nucleoporin Nup1p to the Saccharomyces cerevisiae importin‐beta homologue, Kap95p. Journal of Molecular Biology 349 (3): 515–525.

Makhnevych T, Lusk CP, Anderson AM, Aitchison JD and Wozniak RW (2003) Cell cycle regulated transport controlled by alterations in the nuclear pore complex. Cell 115 (7): 813–823.

Matsuura Y and Stewart M (2005) Nup50/Npap60 function in nuclear protein import complex disassembly and importin recycling. EMBO Journal 24 (21): 3681–3689.

Matsuura Y and Stewart M (2004) Structural basis for the assembly of a nuclear export complex. Nature 432 (7019): 872–877.

Moll UM, Riou G and Levine AJ (1992) Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion. Proceedings of the National Academy of Sciences of the United States of America 89 (15): 7262–7266.

Ohno M, Segref A, Bachi A, Wilm M and Mattaj IW (2000) PHAX, a mediator of U snRNA nuclear export whose activity is regulated by phosphorylation. Cell 101 (2): 187–198.

Pemberton LF and Paschal BM (2005) Mechanisms of receptor‐mediated nuclear import and nuclear export. Traffic 6 (3): 187–198.

Pouton CW, Wagstaff KM, Roth DM, Moseley GW and Jans DA (2007) Targeted delivery to the nucleus. Advanced Drug Delivery Reviews 59 (8): 698–717.

Powers MA, Forbes DJ, Dahlberg JE and Lund E (1997) The vertebrate GLFG nucleoporin, Nup98, is an essential component of multiple RNA export pathways. Journal of Cell Biology 136: 241–250.

Shaw DJ, Eggleton P and Young PJ (2008) Joining the dots: production, processing and targeting of U snRNP to nuclear bodies. Biochimica et Biophysica Acta 1783 (11): 2137–2144.

Simos G and Hurt E (1999) Transfer RNA biogenesis: a visa to leave the nucleus. Current Biology 9: R238–R241.

Smith WA, Schurter BT, Wong‐Staal F and David M (2004) Arginine methylation of RNA helicase a determines its subcellular localization. Journal of Biological Chemistry 279 (22): 22795–22798.

Terry LJ, Shows EB and Wente SR (2007) Crossing the nuclear envelope: hierarchical regulation of nucleocytoplasmic transport. Science 318 (5855): 1414–1416.

Tran EJ, King MC and Corbett AH (2014a) Macromolecular transport between the nucleus and the cytoplasm: advances in mechanism and emerging links to disease. Biochimica et Biophysica Acta 1843 (11): 2784–2795.

Trotman LC, Wang X, Alimonti A, et al. (2007) Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128 (1): 141–156.

Vetter IR, Arndt A, Kutay U, Görlich D and Wittinghofer A (1999) Structural view of the Ran‐importin beta interaction at 2.3 Å resolution. Cell 97: 635–646.

Wellmann A, Flemming P, Behrens P, et al. (2001) High expression of the proliferation and apoptosis associated CSE1L/CAS gene in hepatitis and liver neoplasms: correlation with tumor progression. International Journal of Molecular Medicine 7 (5): 489–494.

Wen W, Meinkoth JL, Tsien RY and Taylor SS (1995) Identification of a signal for rapid export of proteins from the nucleus. Cell 82: 463–473.

Winey M, Yarar D, Giddings TH Jr and Mastronarde DN (1997) Nuclear pore complex number and distribution throughout the Saccharomyces cerevisiae cell cycle by three‐dimensional reconstruction from electron micrographs of nuclear envelopes. Molecular Biology of the Cell 8 (11): 2119–2132.

Yao W, Roser D, Köhler A, et al. (2007) Nuclear export of ribosomal 60S subunits by the general mRNA export receptor Mex67‐Mtr2. Molecular Cell 26 (1): 15–62.

Further Reading

Björk P and Wieslander L (2014) 2014 mechanisms of mRNA export. Seminars in Cell & Developmental Biology 32: 47–54.

Butin‐Israeli V, Adam SA, Goldman AE and Goldman RD (2012) Nuclear lamin functions and disease. Trends in Genetics 28: 464–471.

Cook A, Bono F, Jinek M and Conti E (2007) Structural biology of nucleocytoplasmic transport. Annual Review of Biochemistry 76: 647–671.

Davis JR, Kakar M and Lim CS (2007) Controlling protein compartmentalization to overcome disease. Pharmaceutical Research 24: 17–27.

Fernandez‐Martinez J and Rout MP (2012) A jumbo problem: mapping the structure and functions of the nuclear pore complex. Current Opinion in Cell Biology 24: 92–99.

Görlich D and Kutay U (1999) Transport between the cell nucleus and the cytoplasm. Annual Review of Cell and Developmental Biology 15: 607–660.

Kimura M and Imamoto N (2014) Biological significance of the importin‐β family‐dependent nucleocytoplasmic transport pathways. Traffic 15: 727–748.

Lange A, Mills RE, Lange CJ, et al. (2007) Classical nuclear localization signals: definition, function, and interaction with importin alpha. Journal of Biological Chemistry 282: 5101–5105.

Stewart M (2010) Nuclear export of mRNA. Trends in Biochemical Sciences 35: 609–617.

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. [doi: 10.1002/9780470015902.a0001351.pub3]