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Draft:Viral Ribonucleoprotein

From Wikipedia, the free encyclopedia

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 encapsidating viral RNA, facilitating genome replication and transcription, organizing viral ribonucleoprotein (vRNP) complexes, and evading host immunity.

Structure and function

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Key functions of viral NPs include:

  • RNA Encapsulation: NPs coat the viral genome in a sequence-independent manner, protecting it from nucleases and host pattern recognition receptors such as RIG-I and MDA5.[1]
  • RNP Assembly: NP-RNA complexes serve as templates for viral RNA synthesis by the RNA-dependent RNA polymerase (RdRp).[2][3]
  • Regulation of Replication: NP levels help determine the balance between transcription and genome replication.[4]
  • Virion Assembly: NP interacts with matrix proteins and other structural elements during packaging into virions.[5]

Examples by virus family

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Orthomyxoviridae (e.g., Influenza Virus)

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Influenza A virus NP (~56 kDa) encapsidates 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)

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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)

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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)

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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

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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

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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

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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

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  1. ^ a b Weber M, Weber F. RIG-I-like receptors and negative-strand RNA viruses: RLRly bird catches some worms. Cytokine Growth Factor Rev. 2014 Oct;25(5):621-8. doi: 10.1016/j.cytogfr.2014.05.004. Epub 2014 May 20. PMID: 24894317; PMCID: PMC7108359.
  2. ^ Arranz R, Coloma R, Chichón FJ, Conesa JJ, Carrascosa JL, Valpuesta JM, Ortín J, Martín-Benito J. The structure of native influenza virion ribonucleoproteins. Science. 2012 Dec 21;338(6114):1634-7. doi: 10.1126/science.1228172. Epub 2012 Nov 22. PMID: 23180776.
  3. ^ a b c Lo CY, Tang YS, Shaw PC. Structure and Function of Influenza Virus Ribonucleoprotein. Subcell Biochem. 2018;88:95-128. doi: 10.1007/978-981-10-8456-0_5. PMID: 29900494.
  4. ^ a b Portela, A., & Digard, P. (2002). The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication. Journal of General Virology, 83(4), 723–734. https://doi.org/10.1099/0022-1317-83-4-723
  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. Viral RNA-binding ability conferred by SUMOylation at PB1 K612 of influenza A virus is essential for viral pathogenesis and transmission. PLoS Pathog. 2021 Feb 11;17(2):e1009336. doi: 10.1371/journal.ppat.1009336. PMID: 33571308; PMCID: PMC7904188.
  7. ^ Witwit, H., & de la Torre, J. C. (2025). Mammarenavirus Z Protein Myristoylation and Oligomerization Are Not Required for Its Dose-Dependent Inhibitory Effect on vRNP Activity. Biochem, 5(2), 10. https://doi.org/10.3390/biochem5020010
  8. ^ a b Witwit, H., et al. (2024). Activation of protein kinase receptor (PKR) plays a pro-viral role in mammarenavirus-infected cells. Journal of Virology, 98(3), e01883-23. https://doi.org/10.1128/jvi.01883-23
  9. ^ Hastie KM, King LB, Zandonatti MA, Saphire EO. Structural basis for the dsRNA specificity of the Lassa virus NP exonuclease. PLoS One. 2012;7(8):e44211. doi: 10.1371/journal.pone.0044211. Epub 2012 Aug 28. PMID: 22937163; PMCID: PMC3429428.
  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. Structure of the Lassa virus nucleoprotein revealed by X-ray crystallography, small-angle X-ray scattering, and electron microscopy. J Biol Chem. 2011 Nov 4;286(44):38748-38756. doi: 10.1074/jbc.M111.278838. Epub 2011 Sep 14. PMID: 21917929; PMCID: PMC3207459.
  11. ^ Knopp KA, Ngo T, Gershon PD, Buchmeier MJ2015.Single Nucleoprotein Residue Modulates Arenavirus Replication Complex Formation. mBio6:10.1128/mbio.00524-15.https://doi.org/10.1128/mbio.00524-15
  12. ^ Kirchdoerfer RN, Abelson DM, Li S, Wood MR, Saphire EO. Assembly of the Ebola Virus Nucleoprotein from a Chaperoned VP35 Complex. Cell Rep. 2015 Jul 7;12(1):140-149. doi: 10.1016/j.celrep.2015.06.003. Epub 2015 Jun 25. PMID: 26119732; PMCID: PMC4500542.
  13. ^ A. Desfosses, S. Milles, M.R. Jensen, S. Guseva, J. Colletier, D. Maurin, G. Schoehn, I. Gutsche, R.W.H. Ruigrok, & M. Blackledge, 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) 4256-4264, https://doi.org/10.1073/pnas.1816417116 (2019).
  14. ^ a b Brownsword MJ, Locker N. A little less aggregation a little more replication: Viral manipulation of stress granules. Wiley Interdiscip Rev RNA. 2023 Jan;14(1):e1741. doi: 10.1002/wrna.1741. Epub 2022 Jun 16. Erratum in: Wiley Interdiscip Rev RNA. 2023 Nov-Dec;14(6):e1821. doi: 10.1002/wrna.1821. PMID: 35709333; PMCID: PMC10078398.
  15. ^ Burbelo PD, Riedo FX, Morishima C, Rawlings S, Smith D, Das S, Strich JR, Chertow DS, Davey RT Jr, Cohen JI. Detection of Nucleocapsid Antibody to SARS-CoV-2 is More Sensitive than Antibody to Spike Protein in COVID-19 Patients. medRxiv [Preprint]. 2020 Apr 24:2020.04.20.20071423. doi: 10.1101/2020.04.20.20071423. Update in: J Infect Dis. 2020 Jun 29;222(2):206-213. doi: 10.1093/infdis/jiaa273. PMID: 32511445; PMCID: PMC7239070.
  16. ^ Nachbagauer, R., Liu, WC., Choi, A. et al. A universal influenza virus vaccine candidate confers protection against pandemic H1N1 infection in preclinical ferret studies. npj Vaccines 2, 26 (2017). https://doi.org/10.1038/s41541-017-0026-4



References

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