Viral nucleoprotein

Viral nucleoproteins (NPs) are essential RNA-binding proteins encoded by many viruses, especially negative-sense single-stranded RNA (–ssRNA) viruses. They play crucial roles in encapsulating viral RNA, facilitating genome replication and transcription, organizing viral ribonucleoprotein (vRNP) complexes, and evading host immunity.

Structure and function

Key functions of viral NPs include:

Examples by virus family

Orthomyxoviridae (e.g., Influenza Virus)

Influenza A virus NP (~56 kDa) encapsulates the segmented viral RNA genome into helical RNPs alongside the viral polymerase complex (PA, PB1, PB2). These RNPs are transported into the host nucleus, where viral replication and transcription take place.[3] NP mediates nuclear trafficking via interactions with importins and CRM1.[4] It also undergoes post-translational modifications such as SUMOylation that modulate its function.[6]

Arenaviridae (e.g., Lassa Virus, LCMV)

Mammarenaviruses, including Lassa virus and LCMV, encode a multifunctional NP that plays central roles in genome encapsidation, replication, and immune evasion. NP interacts with the matrix Z protein, and recent research showed that Z protein myristoylation and oligomerization are not required for its dose-dependent inhibition of NP-RNP activity.[7]

Notably, mammarenavirus NP also exploits the host protein kinase R (PKR) pathway, usually antiviral, to support viral replication; PKR activation appears to promote viral growth.[8] The arenaviral nucleoprotein contains a C-terminal exonuclease domain (ExoN) that degrades immunostimulatory double-stranded RNA (dsRNA), helping the virus evade RIG-I-mediated interferon responses.[9]

Structural studies reveal NP forms heptameric ring-like oligomers, a unique arrangement necessary for stable RNA binding and polymerase recruitment.[10] Furthermore, phosphorylation of specific NP residues has been shown to affect replication complex assembly and RNA synthesis efficiency.[11]

Filoviridae (e.g., Ebola Virus)

Ebola virus NP oligomerizes on the viral RNA to form a tightly coiled nucleocapsid, recruiting VP35, VP30, and L polymerase to constitute the replication complex. These complexes are organized into inclusion bodies within the cytoplasm and are essential for viral transcription.[12]

Paramyxoviridae (e.g., Measles Virus)

Measles virus NP binds the viral genome with six-nucleotide periodicity to form left-handed helical nucleocapsids. NP interacts with phosphoprotein (P) and polymerase (L) to regulate transcription and replication.[13]

Host interaction and immune evasion

NPs have evolved to manipulate host antiviral defenses:

  • Interferon Antagonism: Influenza A NP can bind TRIM25 and suppress RIG-I activation, reducing type I interferon production.[1]
  • Stress Granule Disruption: SARS-CoV-2 NP interferes with stress granule assembly by interacting with G3BP1, impairing cellular antiviral responses.[14]
  • PKR Modulation: In mammarenaviruses, NP indirectly leverages PKR signaling to enhance viral replication, representing a rare case of pro-viral PKR activation.[8]

Structural insights

Structural biology has provided important insights into NP function:

  • Influenza NP forms a crescent-shaped structure that oligomerizes via a tail-loop insertion mechanism to encapsidate RNA.[3]
  • Arenavirus and filovirus NPs assemble into ring-like or helical structures that facilitate cooperative RNA binding and efficient polymerase activity.[10]
  • SARS-CoV-2 NP contains both a structured RNA-binding domain and disordered regions that promote liquid–liquid phase separation, supporting replication compartment formation.[14]

Diagnostic and therapeutic applications

NPs are useful in diagnostics and immunization:

  • Diagnostics: Due to their abundance and immunogenicity, NPs are widely used in antigen and antibody tests (e.g., SARS-CoV-2, influenza).[15]
  • Vaccines: NP-based vaccines elicit robust T cell responses, and influenza vaccines incorporating NP can offer broad cross-strain protection.[16]

References

  1. ^ a b Weber M, Weber F (October 2014). "RIG-I-like receptors and negative-strand RNA viruses: RLRly bird catches some worms". Cytokine Growth Factor Rev. 25 (5): 621–8. doi:10.1016/j.cytogfr.2014.05.004. PMC 7108359. PMID 24894317.
  2. ^ Arranz R, Coloma R, Chichón FJ, Conesa JJ, Carrascosa JL, Valpuesta JM, Ortín J, Martín-Benito J (December 2012). "The structure of native influenza virion ribonucleoproteins". Science. 338 (6114): 1634–7. Bibcode:2012Sci...338.1634A. doi:10.1126/science.1228172. PMID 23180776.
  3. ^ a b c Lo CY, Tang YS, Shaw PC (2018). "Structure and Function of Influenza Virus Ribonucleoprotein". Virus Protein and Nucleoprotein Complexes. Subcellular Biochemistry. Vol. 88. Singapore: Springer. pp. 95–128. doi:10.1007/978-981-10-8456-0_5. ISBN 978-981-10-8455-3. PMID 29900494.
  4. ^ a b Portela A, Digard P (April 2002). "The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication". J Gen Virol. 83 (Pt 4): 723–734. doi:10.1099/0022-1317-83-4-723. PMID 11907320.
  5. ^ Riedel, S., et al. (2021). Structural insights into viral nucleoprotein-RNA interactions. Virology, 562, 17–29. https://doi.org/10.1016/j.virol.2021.06.001
  6. ^ Li J, Liang L, Jiang L, Wang Q, Wen X, Zhao Y, Cui P, Zhang Y, Wang G, Li Q, Deng G, Shi J, Tian G, Zeng X, Jiang Y, Liu L, Chen H, Li C (February 2021). "Viral RNA-binding ability conferred by SUMOylation at PB1 K612 of influenza A virus is essential for viral pathogenesis and transmission". PLOS Pathog. 17 (2): e1009336. doi:10.1371/journal.ppat.1009336. PMC 7904188. PMID 33571308.
  7. ^ Witwit H, de la Torre JC (2025). "Mammarenavirus Z Protein Myristoylation and Oligomerization Are Not Required for Its Dose-Dependent Inhibitory Effect on vRNP Activity". Biochem. 5 (2): 10. doi:10.3390/biochem5020010. PMC 12163724. PMID 40520408.
  8. ^ a b Witwit H, Khafaji R, Salaniwal A, Kim AS, Cubitt B, Jackson N, Ye C, Weiss SR, Martinez-Sobrido L, de la Torre JC (March 2024). "Activation of protein kinase receptor (PKR) plays a pro-viral role in mammarenavirus-infected cells". J Virol. 98 (3): e0188323. doi:10.1128/jvi.01883-23. PMC 10949842. PMID 38376197.
  9. ^ Hastie KM, King LB, Zandonatti MA, Saphire EO (2012). "Structural basis for the dsRNA specificity of the Lassa virus NP exonuclease". PLOS ONE. 7 (8): e44211. Bibcode:2012PLoSO...744211H. doi:10.1371/journal.pone.0044211. PMC 3429428. PMID 22937163.
  10. ^ a b Brunotte L, Kerber R, Shang W, Hauer F, Hass M, Gabriel M, Lelke M, Busch C, Stark H, Svergun DI, Betzel C, Perbandt M, Günther S (November 2011). "Structure of the Lassa virus nucleoprotein revealed by X-ray crystallography, small-angle X-ray scattering, and electron microscopy". J Biol Chem. 286 (44): 38748–56. doi:10.1074/jbc.M111.278838. PMC 3207459. PMID 21917929.
  11. ^ Knopp KA, Ngo T, Gershon PD, Buchmeier MJ (April 2015). "Single nucleoprotein residue modulates arenavirus replication complex formation". mBio. 6 (3): e00524–15. doi:10.1128/mBio.00524-15. PMC 4436057. PMID 25922393.
  12. ^ Kirchdoerfer RN, Abelson DM, Li S, Wood MR, Saphire EO (July 2015). "Assembly of the Ebola Virus Nucleoprotein from a Chaperoned VP35 Complex". Cell Rep. 12 (1): 140–9. doi:10.1016/j.celrep.2015.06.003. PMC 4500542. PMID 26119732.
  13. ^ Desfosses A, Milles S, Jensen MR, Guseva S, Colletier JP, Maurin D, Schoehn G, Gutsche I, Ruigrok RW, Blackledge M (March 2019). "Assembly and cryo-EM structures of RNA-specific measles virus nucleocapsids provide mechanistic insight into paramyxoviral replication". Proc Natl Acad Sci U S A. 116 (10): 4256–64. Bibcode:2019PNAS..116.4256D. doi:10.1073/pnas.1816417116. PMC 6410849. PMID 30787192.
  14. ^ a b Brownsword MJ, Locker N (January 2023). "A little less aggregation a little more replication: Viral manipulation of stress granules". Wiley Interdiscip Rev RNA. 14 (1): e1741. doi:10.1002/wrna.1741. PMC 10078398. PMID 35709333.
  15. ^ Burbelo, Peter D.; Riedo, Francis X.; Morishima, Chihiro; Rawlings, Stephen; Smith, Davey; Das, Sanchita; Strich, Jeffrey R.; Chertow, Daniel S.; Davey, Richard T.; Cohen, Jeffrey I. (2020). "Sensitivity in Detection of Antibodies to Nucleocapsid and Spike Proteins of Severe Acute Respiratory Syndrome Coronavirus 2 in Patients with Coronavirus Disease 2019". The Journal of Infectious Diseases. 222 (2): 206–213. doi:10.1093/infdis/jiaa273. medRxiv 10.1101/2020.04.20.20071423. PMC 7313936. PMID 32427334.
  16. ^ Nachbagauer R, Liu WC, Choi A, Wohlbold TJ, Atlas T, Rajendran M, Solórzano A, Berlanda-Scorza F, García-Sastre A, Palese P, Albrecht RA, Krammer F (2017). "A universal influenza virus vaccine candidate confers protection against pandemic H1N1 infection in preclinical ferret studies". npj Vaccines. 2 (1): 26. doi:10.1038/s41541-017-0026-4. PMC 5627297. PMID 29263881.
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