Nucleolin Regulates the Expression of Kaposi's Sarcoma-Associated Herpesvirus' Latency-Associated Nuclear Antigen Through G-Quadruplexes in the MRNA

Overview

Journal Viruses

Publisher MDPI

Specialty Microbiology

Date 2023 Dec 23

PMID 38140679

Authors

Andrew R Zareie

Subhash C Verma

Affiliations

Soon will be listed here.

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes life-long latent infection and is linked to several human malignancies. Latency-associated nuclear antigen (LANA) is highly expressed during latency, and is responsible for the replication and maintenance of the viral genome. The expression of LANA is regulated at transcriptional/translational levels through multiple mechanisms, including the secondary structures in the mRNA sequence. LANA mRNA has multiple G-quadruplexes (G4s) that are bound by multiple proteins to stabilize/destabilize these secondary structures for regulating LANA. In this manuscript, we demonstrate the role of Nucleolin (NCL) in regulating LANA expression through its interaction with G-quadruplexes of LANA mRNA. This interaction reduced LANA's protein expression through the sequestration of mRNA into the nucleus, demonstrated by the colocalization of G4-carrying mRNA with NCL. Furthermore, the downregulation of NCL, by way of a short hairpin, showed an increase in LANA translation following an alteration in the levels of LANA mRNA in the cytoplasm. Overall, the data presented in this manuscript showed that G-quadruplexes-mediated translational control could be regulated by NCL, which can be exploited for controlling KSHV latency.

Citing Articles

G-Quadruplexes in the Regulation of Viral Gene Expressions and Their Impacts on Controlling Infection.

Zareie A, Dabral P, Verma S Pathogens. 2024; 13(1).

PMID: 38251367 PMC: 10819198. DOI: 10.3390/pathogens13010060.

References

Nador R, Cesarman E, Chadburn A, Dawson D, Ansari M, Sald J . Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood. 1996; 88(2):645-56. View

Neidle S, Read M . G-quadruplexes as therapeutic targets. Biopolymers. 2001; 56(3):195-208. DOI: 10.1002/1097-0282(2000)56:3<195::AID-BIP10009>3.0.CO;2-5. View

Dabral P, Babu J, Zareie A, Verma S . LANA and hnRNP A1 Regulate the Translation of LANA mRNA through G-Quadruplexes. J Virol. 2019; 94(3). PMC: 7000962. DOI: 10.1128/JVI.01508-19. View

Abdelmohsen K, Tominaga K, Lee E, Srikantan S, Kang M, Kim M . Enhanced translation by Nucleolin via G-rich elements in coding and non-coding regions of target mRNAs. Nucleic Acids Res. 2011; 39(19):8513-30. PMC: 3201861. DOI: 10.1093/nar/gkr488. View

Bhattacharyya D, Mirihana Arachchilage G, Basu S . Metal Cations in G-Quadruplex Folding and Stability. Front Chem. 2016; 4:38. PMC: 5016522. DOI: 10.3389/fchem.2016.00038. View

Sadagopan S, Sharma-Walia N, Veettil M, Bottero V, Levine R, Vart R . Kaposi's sarcoma-associated herpesvirus upregulates angiogenin during infection of human dermal microvascular endothelial cells, which induces 45S rRNA synthesis, antiapoptosis, cell proliferation, migration, and angiogenesis. J Virol. 2009; 83(7):3342-64. PMC: 2655544. DOI: 10.1128/JVI.02052-08. View

Jeong J, Orvis J, Kim J, McMurtrey C, Renne R, Dittmer D . Regulation and autoregulation of the promoter for the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J Biol Chem. 2004; 279(16):16822-31. DOI: 10.1074/jbc.M312801200. View

Paudel N, Sadagopan S, Chakraborty S, Sarek G, Ojala P, Chandran B . Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with multifunctional angiogenin to utilize its antiapoptotic functions. J Virol. 2012; 86(11):5974-91. PMC: 3372210. DOI: 10.1128/JVI.00070-12. View

Carthew R, Sontheimer E . Origins and Mechanisms of miRNAs and siRNAs. Cell. 2009; 136(4):642-55. PMC: 2675692. DOI: 10.1016/j.cell.2009.01.035. View

10.

Kwun H, Ramos da Silva S, Shah I, Blake N, Moore P, Chang Y . Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 mimics Epstein-Barr virus EBNA1 immune evasion through central repeat domain effects on protein processing. J Virol. 2007; 81(15):8225-35. PMC: 1951309. DOI: 10.1128/JVI.00411-07. View

11.

Ou T, Lu Y, Tan J, Huang Z, Wong K, Gu L . G-quadruplexes: targets in anticancer drug design. ChemMedChem. 2008; 3(5):690-713. DOI: 10.1002/cmdc.200700300. View

12.

Perrone R, Nadai M, Frasson I, Poe J, Butovskaya E, Smithgall T . A dynamic G-quadruplex region regulates the HIV-1 long terminal repeat promoter. J Med Chem. 2013; 56(16):6521-30. PMC: 3791109. DOI: 10.1021/jm400914r. View

13.

Huppert J, Bugaut A, Kumari S, Balasubramanian S . G-quadruplexes: the beginning and end of UTRs. Nucleic Acids Res. 2008; 36(19):6260-8. PMC: 2577360. DOI: 10.1093/nar/gkn511. View

14.

De Leo A, Deng Z, Vladimirova O, Chen H, Dheekollu J, Calderon A . LANA oligomeric architecture is essential for KSHV nuclear body formation and viral genome maintenance during latency. PLoS Pathog. 2019; 15(1):e1007489. PMC: 6364946. DOI: 10.1371/journal.ppat.1007489. View

15.

Kochan J, Wawro M, Kasza A . Simultaneous detection of mRNA and protein in single cells using immunofluorescence-combined single-molecule RNA FISH. Biotechniques. 2015; 59(4):209-12, 214, 216 passim. DOI: 10.2144/000114340. View

16.

Song J, Perreault J, Topisirovic I, Richard S . RNA G-quadruplexes and their potential regulatory roles in translation. Translation (Austin). 2017; 4(2):e1244031. PMC: 5173311. DOI: 10.1080/21690731.2016.1244031. View

17.

Blake N . Immune evasion by gammaherpesvirus genome maintenance proteins. J Gen Virol. 2010; 91(Pt 4):829-46. DOI: 10.1099/vir.0.018242-0. View

18.

Murat P, Zhong J, Lekieffre L, Cowieson N, Clancy J, Preiss T . G-quadruplexes regulate Epstein-Barr virus-encoded nuclear antigen 1 mRNA translation. Nat Chem Biol. 2014; 10(5):358-64. PMC: 4188979. DOI: 10.1038/nchembio.1479. View

19.

Kharel P, Balaratnam S, Beals N, Basu S . The role of RNA G-quadruplexes in human diseases and therapeutic strategies. Wiley Interdiscip Rev RNA. 2019; 11(1):e1568. DOI: 10.1002/wrna.1568. View

20.

Lama L, Seidl C, Ryan K . New insights into the promoterless transcription of DNA coligo templates by RNA polymerase III. Transcription. 2015; 5(2):e27913. PMC: 4214238. DOI: 10.4161/trns.27913. View