Login Register Cart 0
Generic placeholder image

Protein & Peptide Letters

Editor-in-Chief

ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Effects of Glutathionylation on Guanylyltransferase Activity of NS5 N-terminal Capping Domain from Dengue, Japanese Encephalitis, and Zika Viruses

Author(s): Chonticha Saisawang*, Onrapak Reamtong, Isara Nachampa, Patchareebhorn Petcharat, Suphansa Priewkhiew, Somsri Sakdee, Jantana Wongsantichon and Albert J. Ketterman

Volume 30, Issue 5, 2023

Published on: 08 May, 2023

Page: [439 - 447] Pages: 9

DOI: 10.2174/0929866530666230418101606

Price: $65

conference banner
Abstract

Background: Glutathionylation is a protein post-translational modification triggered by oxidative stress. The susceptible proteins are modified by the addition of glutathione to specific cysteine residues. Virus infection also induces oxidative stress in the cell, which affects cellular homeostasis. It is not just the cellular proteins but the viral proteins that can also be modified by glutathionylation events, thereby impacting the function of the viral proteins.

Objectives: This study was conducted to identify the effects of modification by glutathionylation on the guanylyltransferase activity of NS5 and identify the cysteine residues modified for the three flavivirus NS5 proteins.

Methods: The capping domain of NS5 proteins from 3 flaviviruses was cloned and expressed as recombinant proteins. A gel-based assay for guanylyltransferase activity was performed using a GTP analog labeled with the fluorescent dye Cy5 as substrate. The protein modification by glutathionylation was induced by GSSG and evaluated by western blot. The reactive cysteine residues were identified by mass spectrometry.

Results: It was found that the three flavivirus proteins behaved in a similar fashion with increasing glutathionylation yielding decreased guanylyltransferase activity. The three proteins also possessed conserved cysteines and they appeared to be modified for all three proteins.

Conclusion: The glutathionylation appeared to induce conformational changes that affect enzyme activity. The conformational changes might also create binding sites for host cell protein interactions at later stages of viral propagation with the glutathionylation event, thereby serving as a switch for function change.

« Previous
Graphical Abstract

[1]
Kraemer, M.U.G.; Sinka, M.E.; Duda, K.A.; Mylne, A.; Shearer, F.M.; Brady, O.J.; Messina, J.P.; Barker, C.M.; Moore, C.G.; Carvalho, R.G.; Coelho, G.E.; Van Bortel, W.; Hendrickx, G.; Schaffner, F.; Wint, G.R.W.; Elyazar, I.R.F.; Teng, H.J.; Hay, S.I. The global compendium of Aedes aegypti and Ae. albopictus occurrence. Sci. Data, 2015, 2(1), 150035.
[http://dx.doi.org/10.1038/sdata.2015.35] [PMID: 26175912]
[2]
Hamel, R.; Liégeois, F.; Wichit, S.; Pompon, J.; Diop, F.; Talignani, L.; Thomas, F.; Desprès, P.; Yssel, H.; Missé, D. Zika virus: Epidemiology, clinical features and host-virus interactions. Microbes Infect., 2016, 18(7-8), 441-449.
[http://dx.doi.org/10.1016/j.micinf.2016.03.009] [PMID: 27012221]
[3]
Campbell, G.L.; Hills, S.L.; Fischer, M.; Jacobson, J.A.; Hoke, C.H.; Hombach, J.M. Estimated global incidence of Japanese encephalitis: A systematic review. Bull. World Health Organ., 2011, 89(10), 766-774.
[http://dx.doi.org/10.2471/BLT.10.085233]
[4]
Saxena, S.K.; Kumar, S.; Maurya, V.K.; Bhatt, M.L.B. The global distribution and burden of dengue and japanese encephalitis co-infection in acute encephalitis syndrome.In: Current Topics in Neglected Tropical Diseases; Rodriguez-Morales, A.J., Ed.; IntechOpen: Rijeka, 2019.
[http://dx.doi.org/10.5772/intechopen.89792]
[5]
Bhatt, S.; Gething, P.W.; Brady, O.J.; Messina, J.P.; Farlow, A.W.; Moyes, C.L.; Drake, J.M.; Brownstein, J.S.; Hoen, A.G.; Sankoh, O.; Myers, M.F.; George, D.B.; Jaenisch, T.; Wint, G.R.W.; Simmons, C.P.; Scott, T.W.; Farrar, J.J.; Hay, S.I. The global distribution and burden of dengue. Nature, 2013, 496(7446), 504-507.
[http://dx.doi.org/10.1038/nature12060] [PMID: 23563266]
[6]
Brady, O.J.; Gething, P.W.; Bhatt, S.; Messina, J.P.; Brownstein, J.S.; Hoen, A.G.; Moyes, C.L.; Farlow, A.W.; Scott, T.W.; Hay, S.I. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl. Trop. Dis., 2012, 6(8), e1760.
[http://dx.doi.org/10.1371/journal.pntd.0001760] [PMID: 22880140]
[7]
WHO. Countries and territories with current or previous Zika virus transmission Updated. 2019. Available From: https://www.who.int/emergencies/diseases/zika/countries-with-zika-and-vectors-table.pdf
[8]
Mazeaud, C.; Freppel, W.; Chatel-Chaix, L. The Multiples Fates of the Flavivirus RNA Genome During Pathogenesis. Front. Genet., 2018, 9, 595.
[http://dx.doi.org/10.3389/fgene.2018.00595] [PMID: 30564270]
[9]
Garcia-Blanco, M.A.; Vasudevan, S.G.; Bradrick, S.S.; Nicchitta, C. Flavivirus RNA transactions from viral entry to genome replication. Antiviral Res., 2016, 134, 244-249.
[http://dx.doi.org/10.1016/j.antiviral.2016.09.010] [PMID: 27666184]
[10]
Egloff, M.P.; Benarroch, D.; Selisko, B.; Romette, J.L.; Canard, B. An RNA cap (nucleoside-2′-O-)-methyltransferase in the flavivirus RNA polymerase NS5: Crystal structure and functional characterization. EMBO J., 2002, 21(11), 2757-2768.
[http://dx.doi.org/10.1093/emboj/21.11.2757] [PMID: 12032088]
[11]
Ray, D.; Shah, A.; Tilgner, M.; Guo, Y.; Zhao, Y.; Dong, H.; Deas, T.S.; Zhou, Y.; Li, H.; Shi, P.Y. West Nile virus 5′-cap structure is formed by sequential guanine N-7 and ribose 2′-O methylations by nonstructural protein 5. J. Virol., 2006, 80(17), 8362-8370.
[http://dx.doi.org/10.1128/JVI.00814-06] [PMID: 16912287]
[12]
Klema, V.; Padmanabhan, R.; Choi, K. Flaviviral replication complex: Coordination between RNA synthesis and 5′-RNA capping. Viruses, 2015, 7(8), 4640-4656.
[http://dx.doi.org/10.3390/v7082837] [PMID: 26287232]
[13]
Klema, V.J.; Ye, M.; Hindupur, A.; Teramoto, T.; Gottipati, K.; Padmanabhan, R.; Choi, K.H. Dengue virus nonstructural protein 5 (NS5) assembles into a dimer with a unique methyltransferase and polymerase interface. PLoS Pathog., 2016, 12(2), e1005451.
[http://dx.doi.org/10.1371/journal.ppat.1005451] [PMID: 26895240]
[14]
Wang, B.; Thurmond, S.; Hai, R.; Song, J. Structure and function of Zika virus NS5 protein: Perspectives for drug design. Cell. Mol. Life Sci., 2018, 75(10), 1723-1736.
[http://dx.doi.org/10.1007/s00018-018-2751-x] [PMID: 29423529]
[15]
Ramanathan, A.; Robb, G.B.; Chan, S.H. mRNA capping: Biological functions and applications. Nucleic Acids Res., 2016, 44(16), 7511-7526.
[http://dx.doi.org/10.1093/nar/gkw551] [PMID: 27317694]
[16]
Issur, M.; Geiss, B.J.; Bougie, I.; Picard-Jean, F.; Despins, S.; Mayette, J.; Hobdey, S.E.; Bisaillon, M. The flavivirus NS5 protein is a true RNA guanylyltransferase that catalyzes a two-step reaction to form the RNA cap structure. RNA, 2009, 15(12), 2340-2350.
[http://dx.doi.org/10.1261/rna.1609709] [PMID: 19850911]
[17]
Hare, D.; Mossman, K.L. Novel paradigms of innate immune sensing of viral infections. Cytokine, 2013, 63(3), 219-224.
[http://dx.doi.org/10.1016/j.cyto.2013.06.001] [PMID: 23800788]
[18]
Reshi, M.L.; Su, Y.C.; Hong, J.R. RNA Viruses: ROS-Mediated Cell Death. Int. J. Cell Biol., 2014, 2014, 1-16.
[http://dx.doi.org/10.1155/2014/467452] [PMID: 24899897]
[19]
Townsend, D.M. S-glutathionylation: Indicator of cell stress and regulator of the unfolded protein response. Mol. Interv., 2007, 7(6), 313-324.
[http://dx.doi.org/10.1124/mi.7.6.7] [PMID: 18199853]
[20]
Xiong, Y.; Uys, J.D.; Tew, K.D.; Townsend, D.M. S-glutathionylation: From molecular mechanisms to health outcomes. Antioxid. Redox Signal., 2011, 15(1), 233-270.
[http://dx.doi.org/10.1089/ars.2010.3540] [PMID: 21235352]
[21]
Morris, D.; Khurasany, M.; Nguyen, T.; Kim, J.; Guilford, F.; Mehta, R.; Gray, D.; Saviola, B.; Venketaraman, V. Glutathione and infection. Biochim. Biophys. Acta, Gen. Subj., 2013, 1830(5), 3329-3349.
[http://dx.doi.org/10.1016/j.bbagen.2012.10.012] [PMID: 23089304]
[22]
Aquilano, K.; Baldelli, S.; Ciriolo, M.R. Glutathione: New roles in redox signaling for an old antioxidant. Front. Pharmacol., 2014, 5, 196.
[http://dx.doi.org/10.3389/fphar.2014.00196] [PMID: 25206336]
[23]
Popov, D. Protein S -glutathionylation: From current basics to targeted modifications. Arch. Physiol. Biochem., 2014, 120(4), 123-130.
[http://dx.doi.org/10.3109/13813455.2014.944544] [PMID: 25112365]
[24]
Zhang, J.; Ye, Z.; Singh, S.; Townsend, D.M.; Tew, K.D. An evolving understanding of the S-glutathionylation cycle in pathways of redox regulation. Free Radic. Biol. Med., 2018, 120, 204-216.
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.03.038] [PMID: 29578070]
[25]
Giustarini, D.; Rossi, R.; Milzani, A.; Colombo, R.; Dalle-Donne, I. S-Glutathionylation: From redox regulation of protein functions to human diseases. J. Cell. Mol. Med., 2004, 8(2), 201-212.
[http://dx.doi.org/10.1111/j.1582-4934.2004.tb00275.x] [PMID: 15256068]
[26]
Ghezzi, P. ReviewRegulation of protein function by glutathionylation. Free Radic. Res., 2005, 39(6), 573-580.
[http://dx.doi.org/10.1080/10715760500072172] [PMID: 16036334]
[27]
Mieyal, J.J.; Gallogly, M.M.; Qanungo, S.; Sabens, E.A.; Shelton, M.D. Molecular mechanisms and clinical implications of reversible protein S-glutathionylation. Antioxid. Redox Signal., 2008, 10(11), 1941-1988.
[http://dx.doi.org/10.1089/ars.2008.2089] [PMID: 18774901]
[28]
Gallogly, M.M.; Mieyal, J.J. Mechanisms of reversible protein glutathionylation in redox signaling and oxidative stress. Curr. Opin. Pharmacol., 2007, 7(4), 381-391.
[http://dx.doi.org/10.1016/j.coph.2007.06.003] [PMID: 17662654]
[29]
Grek, C.L.; Zhang, J.; Manevich, Y.; Townsend, D.M.; Tew, K.D. Causes and consequences of cysteine S-glutathionylation. J. Biol. Chem., 2013, 288(37), 26497-26504.
[http://dx.doi.org/10.1074/jbc.R113.461368] [PMID: 23861399]
[30]
Pastore, A.; Piemonte, F. S-Glutathionylation signaling in cell biology: Progress and prospects. Eur. J. Pharm. Sci., 2012, 46(5), 279-292.
[http://dx.doi.org/10.1016/j.ejps.2012.03.010] [PMID: 22484331]
[31]
Menon, D.; Board, P.G. A role for glutathione transferase Omega 1 (GSTO1-1) in the glutathionylation cycle. J. Biol. Chem., 2013, 288(36), 25769-25779.
[http://dx.doi.org/10.1074/jbc.M113.487785] [PMID: 23888047]
[32]
Dalle-Donne, I.; Rossi, R.; Colombo, G.; Giustarini, D.; Milzani, A. Protein S-glutathionylation: A regulatory device from bacteria to humans. Trends Biochem. Sci., 2009, 34(2), 85-96.
[http://dx.doi.org/10.1016/j.tibs.2008.11.002] [PMID: 19135374]
[33]
Tew, K.D.; Manevich, Y.; Grek, C.; Xiong, Y.; Uys, J.; Townsend, D.M. The role of glutathione S-transferase P in signaling pathways and S-glutathionylation in cancer. Free Radic. Biol. Med., 2011, 51(2), 299-313.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.04.013] [PMID: 21558000]
[34]
Fratelli, M.; Demol, H.; Puype, M.; Casagrande, S.; Eberini, I.; Salmona, M.; Bonetto, V.; Mengozzi, M.; Duffieux, F.; Miclet, E.; Bachi, A.; Vandekerckhove, J.; Gianazza, E.; Ghezzi, P. Identification by redox proteomics of glutathionylated proteins in oxidatively stressed human T lymphocytes. Proc. Natl. Acad. Sci. USA, 2002, 99(6), 3505-3510.
[http://dx.doi.org/10.1073/pnas.052592699] [PMID: 11904414]
[35]
Su, D.; Gaffrey, M.J.; Guo, J.; Hatchell, K.E.; Chu, R.K.; Clauss, T.R.W.; Aldrich, J.T.; Wu, S.; Purvine, S.; Camp, D.G.; Smith, R.D.; Thrall, B.D.; Qian, W.J. Proteomic identification and quantification of S-glutathionylation in mouse macrophages using resin-assisted enrichment and isobaric labeling. Free Radic. Biol. Med., 2014, 67, 460-470.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.12.004] [PMID: 24333276]
[36]
Gonzalez-Dosal, R.; Horan, K.A.; Rahbek, S.H.; Ichijo, H.; Chen, Z.J.; Mieyal, J.J.; Hartmann, R.; Paludan, S.R. HSV infection induces production of ROS, which potentiate signaling from pattern recognition receptors: Role for S-glutathionylation of TRAF3 and 6. PLoS Pathog., 2011, 7(9), e1002250.
[http://dx.doi.org/10.1371/journal.ppat.1002250] [PMID: 21949653]
[37]
Prinarakis, E.; Chantzoura, E.; Thanos, D.; Spyrou, G. S-glutathionylation of IRF3 regulates IRF3–CBP interaction and activation of the IFNβ pathway. EMBO J., 2008, 27(6), 865-875.
[http://dx.doi.org/10.1038/emboj.2008.28] [PMID: 18309294]
[38]
Saisawang, C.; Kuadkitkan, A.; Auewarakul, P.; Smith, D.R.; Ketterman, A.J. Glutathionylation of dengue and Zika NS5 proteins affects guanylyltransferase and RNA dependent RNA polymerase activities. PLoS One, 2018, 13(2), e0193133.
[http://dx.doi.org/10.1371/journal.pone.0193133] [PMID: 29470500]
[39]
Kovanich, D.; Saisawang, C.; Sittipaisankul, P.; Ramphan, S.; Kalpongnukul, N.; Somparn, P.; Pisitkun, T.; Smith, D.R. Analysis of the zika and japanese encephalitis virus NS5 interactomes. J. Proteome Res., 2019, 18(8), 3203-3218.
[http://dx.doi.org/10.1021/acs.jproteome.9b00318] [PMID: 31199156]
[40]
Mairiang, D.; Zhang, H.; Sodja, A.; Murali, T.; Suriyaphol, P.; Malasit, P.; Limjindaporn, T.; Finley, R.L., Jr Identification of new protein interactions between dengue fever virus and its hosts, human and mosquito. PLoS One, 2013, 8(1), e53535.
[http://dx.doi.org/10.1371/journal.pone.0053535] [PMID: 23326450]
[41]
Olagnier, D.; Peri, S.; Steel, C.; van Montfoort, N.; Chiang, C.; Beljanski, V.; Slifker, M.; He, Z.; Nichols, C.N.; Lin, R.; Balachandran, S.; Hiscott, J. Cellular oxidative stress response controls the antiviral and apoptotic programs in dengue virus-infected dendritic cells. PLoS Pathog., 2014, 10(12), e1004566.
[http://dx.doi.org/10.1371/journal.ppat.1004566] [PMID: 25521078]
[42]
Su, C.I.; Tseng, C.H.; Yu, C.Y.; Lai, M.M.C. SUMO modification stabilizes dengue virus nonstructural protein 5 to support virus replication. J. Virol., 2016, 90(9), 4308-4319.
[http://dx.doi.org/10.1128/JVI.00223-16] [PMID: 26889037]
[43]
Kapoor, M.; Zhang, L.; Ramachandra, M.; Kusukawa, J.; Ebner, K.E.; Padmanabhan, R. Association between NS3 and NS5 proteins of dengue virus type 2 in the putative RNA replicase is linked to differential phosphorylation of NS5. J. Biol. Chem., 1995, 270(32), 19100-19106.
[http://dx.doi.org/10.1074/jbc.270.32.19100] [PMID: 7642575]
[44]
Tay, M.Y.F.; Smith, K.; Ng, I.H.W.; Chan, K.W.K.; Zhao, Y.; Ooi, E.E.; Lescar, J.; Luo, D.; Jans, D.A.; Forwood, J.K.; Vasudevan, S.G. The C-terminal 18 amino acid region of dengue virus NS5 regulates its subcellular localization and contains a conserved arginine residue essential for infectious virus production. PLoS Pathog., 2016, 12(9), e1005886.
[http://dx.doi.org/10.1371/journal.ppat.1005886] [PMID: 27622521]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy