Nuclear localization signal peptides (NLS) and their role in viral pathogenicity


  • Tatiana Nikolaevna Nosalskaya Mechnikov Institute of Microbiology and Immunology,
  • Artur Viktorovich Martynov Mechnikov Institute of Microbiology and Immunology,
  • Tatiana Vasilievna Bomko Mechnikov Institute of Microbiology and Immunology,


Nuclear localization signal, viruses, coronaviruses, influenza, hepatitis, virulence


The review provides data about nuclear localization signal peptides (NLS) and their function in the cell, incl. with a viral infection process. The binding, penetration, assembly, and budding of viruses are currently being intensively studied in many systems. However, the stages of nuclear transport during the penetration and release of the virus have remained practically unexplored. NLS  were first identified in the large T antigen virus SV40 and from nucleoplasmin, and then were identified in a large number of proteins. They usually contain short base peptides includes lysine or arginine residues in the form of mono- or bipartite signals. NLSs include the "pat4" motif, which consists of a contiguous stretch four essential amino acids (arginine and lysine). Both coronaviruses and arteriviruses show similar genomic organization and belong to Nidovirales. Although both families encode nucleoproteins (N-proteins), the main function of which is to bind viral RNA, NLS-containing proteins has different sizes and do not have significant homology. The review provides the characteristics and structure of NLS for many viral proteins, and shows their role in the pathogenicity of viruses.

DOI: 10.5281/zenodo.4382147


Mao Y.S., Zhang B., Spector D.L. Biogenesis and function of nuclear bodies. Trends in Genetics. 2011. 27. №8. Р.295–306.

Boulikas T. Nuclear localization signals (NLS). Critical Rev. Eukaryotic Gene Expression. 1993. 3. №3. Р. 193-227.

Rowland R.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. – 2006. – 95, №1-2. – Р. 23–33.

Zemach A., Li Y., Ben-Meir H., Oliva M., et al. Different Domains Control the Localization and Mobility of like heterochromatin protein1 in Arabidopsis Nuclei W. Plant Cell. 2006. 18. Р. 133–145

Melen K., Kinnunen L., Fagerlund R., et al. Nuclear and Nucleolar Targeting of Influenza A Virus NS1 Protein: Striking Differences between Different Virus Subtypes. J. Virol. 2007. 81. №11. Р. 5995–6006.

Garcia-Bustos J., Heitman J., Hall M.N. Nuclear protein localization. BBA. 1991. 107. №1. Р. 83–101.

Robbins J., Dilwortht S.M., Laskey R.A., Dingwall C. Two interdependent basic domains in nucleoplasmin nuclear targeting sequence: Identification of a class of bipartite nuclear targeting sequence. Cell. 1991. 64. №3. Р.615–623.

Cokol M., Nair R., Rost B. Finding nuclear localization signals . EMBO Reports. 2000. 1, №5. Р. 411–415.

Dingwall C., Laskey R.A. Nuclear targeting sequences — a consensus? Trend Biochem. Sci. 1991. 16. Р. 478–481.

Conti E., Kuriyan J. Crystallographic analysis of the specific yet versatile recognition of distinct nuclear localization signals by karyopherin α . Structure. 2000. 8. №3. Р. 329–338.

Fontes M.R.M., Teh T., Kobe B. Structural basis of recognition of monopartite and bipartite nuclear localization sequences by mammalian importin-α11.Edited by K. Nagai . J Mol. Biol. 2000. 297. №5. Р. 1183–1194.

Hodel M.R., Corbett A.H., Hodel A.E. Dissection of a Nuclear Localization Signal . J. Biol. Chem. 2000. 276. №2. Р. 1317–1325.

Matsuura Y., Stewart M. Nup50/Npap60 function in nuclear protein import complex disassembly and importin recycling. EMBO J. 2005. 24. №21. Р. 3681–3689.

Matsuura Y., Stewart M. Structural basis for the assembly of a nuclear export complex. Nature. 2004. 432. №7019. Р. 872–877.

Gilchrist D., Rexach M. Molecular Basis for the Rapid Dissociation of Nuclear Localization Signals from Karyopherin α in the Nucleoplasm. J. Biol. Chem. 2003. 278. №51. Р. 51937–51949.

Lange A., Mills R.E., Lange C.J., et al. Classical Nuclear Localization Signals: Definition, Function, and Interaction with Importin α. J Biol Chem. 2007. 282. №8. Р. 5101–5105

Boulikas T. Putative Nuclear Localization Signals (NLS) in Protein Transcripti on Factors. J. Cell. Biochem. 1994. 55. Р. 32-58.

Macara I.G. Transport into and out of the Nucleus. Microbiol. Mol. Biol. Rev. 2001. 65. №4. Р. 570-594.

Whittaker G.R. Virus nuclear import . Advanced Drug Del. Rev. 2003. 55. Р. 733- 747.

Jakob R. Electroporation-mediated delivery of nucleolar targeting sequences from Semliki Forest virus nucleocapsid protein . Prep. Biochem. 1995. 25. №3. Р. 99-117.

Michel M.R., Elgizoli M., Dai Y., et al. Karyophilic properties of Semliki Forest virus nucleocapsid protein. J. Virol. 1990. 64. № 10.Р. 5123-5131.

Peranen J., Rikkonen M., Liljestrom P., Kaariainen L. Nuclear localisation of Semliki Forest virus-specific nonstructural protein nsP2 . J. Virol. 1990. 64. № 8. Р.1888-1896.

Favre D., Studer E., Michel M.R. Two nucleolar targeting signals present in the N-temrinal part of Semliki Forest virus capsid protein . Arch. Virol. 1994. 137. № 1-2. Р. 149-155.

Wengler G., Wurkner D., Wengler G. Identification of a sequence element in the alphavirus core protein which mediates interaction of cores with ribosomes and the disassembly of cores. Virol. 1992. 191. №2. Р 880-888.

Fazakerley J.K., Boyd A., Mikkola M.L., Kaariainen L. A single amino acid change in the nuclear localisation sequence of the nsP2 protein affects the neurovirulence of semliki forest virus. J. Virol. 2002. 76. №1. –Р. 392-396.

Hiscox J.A. The interaction of animal cytoplasmic RNA viruses with the nucleus to facilitate replication . Virus Res. 2003. 951. № 1-2. Р. 13–22.

Wurm T., Chen H., Britton P. et al. Localisation to the nucleolus is a common feature of coronavirus nucleoproteins and the protein may disrupt host cell division. J. Virol. 2001. 75. №19. Р. 9345-9356.

Tijms M.A., van der MeerY., SnijderE.J. Nuclear localisation of non-structural protein 1 and nucleocapsid protein of equine arteritis virus . J. Gen. Virol. 2002. 83. Р. 795-800.

O’Neill R.E., Jaskunas R., Blobel G., et al. Nuclear Import of Influenza Virus RNA Can Be Mediated by Viral Nucleoprotein and Transport Factors Required for Protein Import. J. Biol. Chem. 1995. 273. №39. Р. 22701–22704.

Cros J.F., Garcıa-Sastre A., Palese P. An Unconventional NLS is Critical for the Nuclear Import of the Influenza A Virus Nucleoprotein and Ribonucleoprotein . Traffic. 2005. 6. Р. 205–213.

Cunningham M.D., Cleaveland J., Nadler S.G. An intracellular targeted NLS peptide inhibitor of karyopherin α:NF-jB interactions . Biochem. Biophys. Res. Commun. 2003. 300. Р. 403–407.

Ozawa M., Fujii K., Muramoto Y., et al. Contributions of Two Nuclear Localization Signals of Influenza A Virus Nucleoprotein to Viral Replication. J. Virol. 2007. 81. №1. Р. 30–41.

Sun W.W.H., Panté Y.-H.B., N. Nuclear import of influenza A viral ribonucleoprotein complexes is mediated by two nuclear localization sequences on viral nucleoprotein . Virol. J. 2007. 4. №49. Р. 1-12.

Gussow A.B., Auslander N., Faure G., et al. Genomic determinants of pathogenicity in SARS-CoV-2 and other human coronaviruses. Proceedings of the National Academy of Sciences. 2020. Р. 1-7.

You J. Subcellular localization of the severe acute respiratory syndrome coronavirus nucleocapsid protein . J General Virol. 2005. 86. №12. Р. 3303–3310.

McBride R., van Zyl M., Fielding B. The Coronavirus Nucleocapsid Is a Multifunctional Protein . Viruses. 2014. 6. №8. Р. 2991–3018.

Hiscox J.A., Wurm T., Wilson L., et al. The Coronavirus Infectious Bronchitis Virus Nucleoprotein Localizes to the Nucleolus J. Virol. 2001. 75. №1. Р. 506–512.

Timani K.A., Liao Q., Ye L., et al. Nuclear/nucleolar localization properties of C-terminal nucleocapsid protein of SARS сoronavirus. Virus Res. 2005. 114. Р. 23–34.

Xu W., Edwards M.R., Borek D.M., et al. Ebola Virus VP24 Targets a Unique NLS Binding Site on Karyopherin Alpha 5 to Selectively Compete with Nuclear Import of Phosphorylated STAT1. Cell Host Microb. 2014. 16. Р. 187–200.

Xing J., Wang S., Li Y., et al. Characterization of the subcellular localization of herpes simplex virus type 1 proteins in living cells. Med. Microbiol. Immunol. 2010. 200. №1. Р. 61–68.

Cai M., Huang Z., Liao Z., et al. Characterization of the subcellular localization and nuclear import molecular mechanisms of herpes simplex virus 1 UL2. Biol. Chem. 2017. 398. №4. Р. 1-17.

Abaitua F., Hollinshead M., Bolstad M., et al. A Nuclear Localization Signal in Herpesvirus Protein VP1-2 Is Essential for Infection via Capsid Routing to the Nuclear Pore. J. Virol. 2012. 86. №17. Р. 8998–9014.

Li M., Zou X., Wang Y., et al . The nuclear localization signal-mediated nuclear targeting of herpes simplex virus 1 early protein UL2 is important for efficient viral production. AGING. 2020. 12. №3. Р. 2921-2938.

Neufeldt C.J., Joyce M.A., Levin A., et al. Hepatitis C virus-induced cytoplasmic organelles use the nuclear transport machinery to establish an environment conducive to virus replication. PLoS Pathog. 2013. 9. №10. Р. 1-16.

Levin A, Hayouka Z, Friedler A, Loyter A. Over-expression of the HIV-1 Rev promotes death of nondividing eukaryotic cells . Virus Genes. 2010. 40. Р. 341–346.

Levin A, Hayouka Z, Friedler A, Loyter A. Transportin 3 and importin alpha are required for effective nuclear import of HIV-1 integrase in virus-infected cells . Nucleus. 2010. 1. Р. 422–431.

Levin A., Neufeldt C.J., Pang D., et al. Functional Characterization of Nuclear Localization and Export Signals in Hepatitis C Virus Proteins and Their Role in the Membranous Web. PLoS ONE. 2014. 9. №12. Р. 1-36.

Whittaker G.R., Helenius A. Nuclear Import and Export of Viruses and Virus Genomes. . Virol. 1998. 246. №1. Р. 1–23.


How to Cite

Nosalskaya, T. N., Martynov, A. V., & Bomko, T. V. (2020). Nuclear localization signal peptides (NLS) and their role in viral pathogenicity. Annals of Mechnikov’s Institute, (4), 31–40. Retrieved from