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. 2010 Apr 9;25(2):79–85. doi: 10.1007/s12250-010-3099-z

The nucleocytoplasmic transport of viral proteins

Qiong Ding 1, Lei Zhao 1, Hong Guo 1, Alan C Zheng 1,✉
PMCID: PMC8227907  PMID: 20960304

Abstract

Molecules can enter the nucleus by passive diffusion or active transport mechanisms, depending on their size. Small molecules up to size of 50–60 kDa or less than 10 nm in diameter can diffuse passively through the nuclear pore complex (NPC), while most proteins are transported by energy driven transport mechanisms. Active transport of viral proteins is mediated by nuclear localization signals (NLS), which were first identified in Simian Virus 40 large T antigen and had subsequently been identified in a large number of viral proteins. Usually they contain short stretches of lysine or arginine residues. These signals are recognized by the importin super-family (importin α and β) proteins that mediate the transport across the nuclear envelope through Ran-GTP. In contrast, only one class of the leucine-rich nuclear export signal (NES) on viral proteins is known at present. Chromosome region maintenance 1 (CRM1) protein mediates nuclear export of hundreds of viral proteins through the recognition of the leucine-rich NES.

Key words: Nuclear localization signal (NLS), Nuclear export signal (NES), Nuclear pore complex (NPC), Viral proteins

Footnotes

Foundation items: The Startup Fund of the Hundred Talents Program of the Chinese Academy of Science (20071010-141); National Natural Science Foundation of China (30870120); Open Research Fund Program of the State Key Laboratory of Virology of China (2007003, 2009007); Hubei Province Natural Science Foundation of Innovation Groups Project (2008CDA013).

These authors contributed equally to this work.

References

  • 1.Allen T. D., Cronshaw J. M., Bagley S., et al. The nuclear pore complex: mediator of translocation between nucleus and cytoplasm. J Cell Sci. 2000;113(Pt10):1651–1659. doi: 10.1242/jcs.113.10.1651. [DOI] [PubMed] [Google Scholar]
  • 2.Bayliss R., Littlewood T., Stewart M. Structural basis for the interaction between FxFG nucleoporin repeats and importin-beta in nuclear trafficking. Cell. 2000;102:99–108. doi: 10.1016/S0092-8674(00)00014-3. [DOI] [PubMed] [Google Scholar]
  • 3.Boulo S., Akarsu H., Ruigrok R. W., et al. Nuclear traffic of influenza virus proteins and ribonucleoprotein complexes. Virus Res. 2007;124:12–21. doi: 10.1016/j.virusres.2006.09.013. [DOI] [PubMed] [Google Scholar]
  • 4.Bremner K. H., Seymour L. W., Pouton C. W. Harnessing nuclear localization pathways for transgene delivery. Curr Opin Mol Ther. 2001;3:170–177. [PubMed] [Google Scholar]
  • 5.Chen T., Brownawell A. M., Macara I. G. Nucleocytoplasmic shuttling of JAZ, a new cargo protein for exportin-5. Mol Cell Biol. 2004;24:6608–6619. doi: 10.1128/MCB.24.15.6608-6619.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Conti E., Muller C. W., Stewart M. Karyopherin flexibility in nucleocytoplasmic transport. Curr Opin Struct Biol. 2006;16:237–244. doi: 10.1016/j.sbi.2006.03.010. [DOI] [PubMed] [Google Scholar]
  • 7.Dingwall C., Robbins J., Dilworth S. M., et al. The nucleoplasmin nuclear location sequence is larger and more complex than that of SV-40 large T antigen. J Cell Biol. 1988;107:841–849. doi: 10.1083/jcb.107.3.841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Dong X., Biswas A., Suel K. E., et al. Structural basis for leucine-rich nuclear export signal recognition by CRM1. Nature. 2009;458:1136–1141. doi: 10.1038/nature07975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Eulalio A., Nunes-Correia I., Carvalho A. L., et al. Two African swine fever virus proteins derived from a common precursor exhibit different nucleocytoplasmic transport activities. J Virol. 2004;78:9731–9739. doi: 10.1128/JVI.78.18.9731-9739.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Fahrenkrog B., Aebi U. The vertebrate nuclear pore complex: from structure to function. Results Probl Cell Differ. 2002;35:25–48. doi: 10.1007/978-3-540-44603-3_2. [DOI] [PubMed] [Google Scholar]
  • 11.Fornerod M., Ohno M., Yoshida M., et al. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell. 1997;90:1051–1060. doi: 10.1016/S0092-8674(00)80371-2. [DOI] [PubMed] [Google Scholar]
  • 12.Fukuda M., Asano S., Nakamura T., et al. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature. 1997;390:308–311. doi: 10.1038/36894. [DOI] [PubMed] [Google Scholar]
  • 13.Guo H., Ding Q., Lin F., et al. Characterization of the Nuclear and Nucleolar Localization Signals of Bovine Herpesvirus-1 Infected Cell Protein 27. Virus Res. 2009;145:312–320. doi: 10.1016/j.virusres.2009.07.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Hodel M. R., Corbett A. H., Hodel A. E. Dissection of a nuclear localization signal. J Biol Chem. 2001;276:1317–1325. doi: 10.1074/jbc.M008522200. [DOI] [PubMed] [Google Scholar]
  • 15.Kalab P., Weis K., Heald R. Visualization of a Ran-GTP gradient in interphase and mitotic Xenopus egg extracts. Science. 2002;295:2452–2456. doi: 10.1126/science.1068798. [DOI] [PubMed] [Google Scholar]
  • 16.Kalderon D., Richardson W. D., Markham A. F., et al. Sequence requirements for nuclear location of simian virus 40 large-T antigen. Nature. 1984;311:33–38. doi: 10.1038/311033a0. [DOI] [PubMed] [Google Scholar]
  • 17.Kosugi S., Hasebe M., Matsumura N., et al. Six classes of nuclear localization signals specific to different binding grooves of importin alpha. J Biol Chem. 2009;284:478–485. doi: 10.1074/jbc.M807017200. [DOI] [PubMed] [Google Scholar]
  • 18.Kudo N., Matsumori N., Taoka H., et al. Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region. Proc Natl Acad Sci USA. 1999;96:9112–9117. doi: 10.1073/pnas.96.16.9112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.la Cour T., Kiemer L., Molgaard A., et al. Analysis and prediction of leucine-rich nuclear export signals. Protein Eng Des Sel. 2004;17:527–536. doi: 10.1093/protein/gzh062. [DOI] [PubMed] [Google Scholar]
  • 20.Lange A., Mills R. E., Lange C. J., et al. Classical nuclear localization signals: definition, function, and interaction with importin alpha. J Biol Chem. 2007;282:5101–5105. doi: 10.1074/jbc.R600026200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Lee B. J., Cansizoglu A. E., Suel K. E., et al. Rules for nuclear localization sequence recognition by karyopherin beta 2. Cell. 2006;126:543–558. doi: 10.1016/j.cell.2006.05.049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Lee C. H., Chang S. C., Wu C. H., et al. A novel chromosome region maintenance 1-independent nuclear export signal of the large form of hepatitis delta antigen that is required for the viral assembly. J Biol Chem. 2001;276:8142–8148. doi: 10.1074/jbc.M004477200. [DOI] [PubMed] [Google Scholar]
  • 23.Lischka P., Rosorius O., Trommer E., et al. A novel transferable nuclear export signal mediates CRM1-independent nucleocytoplasmic shuttling of the human cytomegalovirus transactivator protein pUL69. EMBO J. 2001;20:7271–7283. doi: 10.1093/emboj/20.24.7271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Michael W. M., Choi M., Dreyfuss G. A nuclear export signal in hnRNP A1: a signal-mediated, temperature-dependent nuclear protein export pathway. Cell. 1995;83:415–422. doi: 10.1016/0092-8674(95)90119-1. [DOI] [PubMed] [Google Scholar]
  • 25.Miyamoto Y., Imamoto N., Sekimoto T., et al. Differential modes of nuclear localization signal (NLS) recognition by three distinct classes of NLS receptors. J Biol Chem. 1997;272:26375–26381. doi: 10.1074/jbc.272.42.26375. [DOI] [PubMed] [Google Scholar]
  • 26.Nair R., Carter P., Rost B. NLSdb: database of nuclear localization signals. Nucleic Acids Res. 2003;31:397–399. doi: 10.1093/nar/gkg001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Ossareh-Nazari B., Bachelerie F., Dargemont C. Evidence for a role of CRM1 in signal-mediated nuclear protein export. Science. 1997;278:141–144. doi: 10.1126/science.278.5335.141. [DOI] [PubMed] [Google Scholar]
  • 28.Ossareh-Nazari B., Dargemont C. Domains of Crm1 involved in the formation of the Crm1, RanGTP, and leucine-rich nuclear export sequences trimeric complex. Exp Cell Res. 1999;252:236–241. doi: 10.1006/excr.1999.4599. [DOI] [PubMed] [Google Scholar]
  • 29.Peters R. Introduction to nucleocytoplasmic transport: molecules and mechanisms. Methods Mol Biol. 2006;322:235–258. doi: 10.1007/978-1-59745-000-3_17. [DOI] [PubMed] [Google Scholar]
  • 30.Quimby B. B., Dasso M. The small GTPase Ran: interpreting the signs. Curr Opin Cell Biol. 2003;15:338–344. doi: 10.1016/S0955-0674(03)00046-2. [DOI] [PubMed] [Google Scholar]
  • 31.Roberts B. L., Richardson W. D., Smith A. E. The effect of protein context on nuclear location signal function. Cell. 1987;50:465–475. doi: 10.1016/0092-8674(87)90500-9. [DOI] [PubMed] [Google Scholar]
  • 32.Rowland R. R., Yoo D. Nucleolar-cytoplasmic shuttling of PRRSV nucleocapsid protein: a simple case of molecular mimicry or the complex regulation by nuclear import, nucleolar localization and nuclear export signal sequences. Virus Res. 2003;95:23–33. doi: 10.1016/S0168-1702(03)00161-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Siomi H., Dreyfuss G. A nuclear localization domain in the hnRNP A1 protein. J Cell Biol. 1995;129:551–560. doi: 10.1083/jcb.129.3.551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Smith A. E., Slepchenko B. M., Schaff J. C., et al. Systems analysis of Ran transport. Science. 2002;295:488–491. doi: 10.1126/science.1064732. [DOI] [PubMed] [Google Scholar]
  • 35.Suel K. E., Chook Y. M. Kap104p imports the PY-NLS-containing transcription factor Tfg2p into the nucleus. J Biol Chem. 2009;284:15416–15424. doi: 10.1074/jbc.M809384200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Zheng C., Brownlie R., Babiuk L. A., et al. Characterization of nuclear localization and export signals of the major tegument protein VP8 of bovine herpesvirus-1. Virology. 2004;324:327–339. doi: 10.1016/j.virol.2004.03.042. [DOI] [PubMed] [Google Scholar]
  • 37.Zheng C., Brownlie R., Babiuk L. A., et al. Characterization of the nuclear localization and nuclear export signals of bovine herpesvirus 1 VP22. J Virol. 2005;79:11864–11872. doi: 10.1128/JVI.79.18.11864-11872.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]

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