Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

US28, a Virally-Encoded GPCR as an Antiviral Target for Human Cytomegalovirus Infection

  • Received : 2016.09.20
  • Accepted : 2016.11.22
  • Published : 2017.01.01
Download PDF
⟨ Previous Next ⟩

Abstract

Viruses continue to evolve a new strategy to take advantage of every aspect of host cells in order to maximize their survival. Due to their central roles in transducing a variety of transmembrane signals, GPCRs seem to be a prime target for viruses to pirate for their own use. Incorporation of GPCR functionality into the genome of herpesviruses has been demonstrated to be essential for pathogenesis of many herpesviruses-induced diseases. Here, we introduce US28 of human cytomegalovirus (HCMV) as the best-studied example of virally-encoded GPCRs to manipulate host GPCR signaling. In this review, we wish to summarize a number of US28-related topics including its regulation of host signaling pathways, its constitutive internalization, its structural and functional analysis, its roles in HCMV biology and pathogenesis, its proliferative activities and role in oncogenesis, and pharmacological modulation of its biological activities. This review will aid in our understanding of how pathogenic viruses usurp the host GPCR signaling for successful viral infection. This kind of knowledge will enable us to build a better strategy to control viral infection by normalizing the virally-dysregulated host GPCR signaling.

Keywords

References

  1. Arvanitakis, L., Geras-Raaka, E., Varma, A., Gershengorn, M. C. and Cesarman, E. (1997) Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 385, 347-350. https://doi.org/10.1038/385347a0
  2. Balkwill, F. (2004) The significance of cancer cell expression of the chemokine receptor CXCR4. Semin. Cancer Biol. 14, 171-179. https://doi.org/10.1016/j.semcancer.2003.10.003
  3. Bhattacharjee, B., Renzette, N. and Kowalik, T. F. (2012) Genetic analysis of cytomegalovirus in malignant gliomas. J. Virol. 86, 6815-6824. https://doi.org/10.1128/JVI.00015-12
  4. Billstrom, M. A., Johnson, G. L., Avdi, N. J. and Worthen, G. S. (1998) Intracellular signaling by the chemokine receptor US28 during human cytomegalovirus infection. J. Virol. 72, 5535-5544.
  5. Billstrom, M. A., Lehman, L. A. and Scott Worthen, G. (1999) Depletion of extracellular RANTES during human cytomegalovirus infection of endothelial cells. Am. J. Respir. Cell Mol. Biol. 21, 163-167. https://doi.org/10.1165/ajrcmb.21.2.3673
  6. Bodaghi, B., Jones, T. R., Zipeto, D., Vita, C., Sun, L., Laurent, L., Arenzana-Seisdedos, F., Virelizier, J. L. and Michelson, S. (1998) Chemokine sequestration by viral chemoreceptors as a novel viral escape strategy: withdrawal of chemokines from the environment of cytomegalovirus-infected cells. J. Exp. Med. 188, 855-866. https://doi.org/10.1084/jem.188.5.855
  7. Bongers, G., Maussang, D., Muniz, L. R., Noriega, V. M., Fraile-Ramos, A., Barker, N., Marchesi, F., Thirunarayanan, N., Vischer, H. F., Qin, L., Mayer, L., Harpaz, N., Leurs, R., Furtado, G. C., Clevers, H., Tortorella, D., Smit, M. J. and Lira, S. A. (2010) The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice. J. Clin. Invest. 120, 3969-3978. https://doi.org/10.1172/JCI42563
  8. Boomker, J. M., van Luyn, M. J., The, T. H., de Leij, L. F. and Harmsen, M. C. (2005) US28 actions in HCMV infection: lessons from a versatile hijacker. Rev. Med. Virol. 15, 269-282. https://doi.org/10.1002/rmv.468
  9. Burg, J. S., Ingram, J. R., Venkatakrishnan, A. J., Jude, K. M., Dukkipati, A., Feinberg, E. N., Angelini, A., Waghray, D., Dror, R. O., Ploegh, H. L. and Garcia, K. C. (2015) Structural biology. Structural basis for chemokine recognition and activation of a viral G proteincoupled receptor. Science 347, 1113-1117. https://doi.org/10.1126/science.aaa5026
  10. Cabrera-Vera, T. M., Vanhauwe, J., Thomas, T. O., Medkova, M., Preininger, A., Mazzoni, M. R. and Hamm, H. E. (2003) Insights into G protein structure, function, and regulation. Endocr. Rev. 24, 765-781. https://doi.org/10.1210/er.2000-0026
  11. Casarosa, P., Bakker, R. A., Verzijl, D., Navis, M., Timmerman, H., Leurs, R. and Smit, M. J. (2001) Constitutive signaling of the human cytomegalovirus-encoded chemokine receptor US28. J. Biol. Chem. 276, 1133-1137. https://doi.org/10.1074/jbc.M008965200
  12. Casarosa, P., Menge, W. M., Minisini, R., Otto, C., van Heteren, J., Jongejan, A., Timmerman, H., Moepps, B., Kirchhoff, F., Mertens, T., Smit, M. J. and Leurs, R. (2003a) Identification of the first nonpeptidergic inverse agonist for a constitutively active viral-encoded G protein-coupled receptor. J. Biol. Chem. 278, 5172-5178. https://doi.org/10.1074/jbc.M210033200
  13. Casarosa, P., Menge, W. M., Minisini, R., Otto, C., van Heteren, J., Jongejan, A., Timmerman, H., Moepps, B., Kirchhoff, F., Mertens, T., Smit, M. J. and Leurs, R. (2003b) Identification of the first nonpeptidergic inverse agonist for a constitutively active viral-encoded G protein-coupled receptor. J. Biol. Chem. 278, 5172-5178. https://doi.org/10.1074/jbc.M210033200
  14. Casarosa, P., Waldhoer, M., LiWang, P. J., Vischer, H. F., Kledal, T., Timmerman, H., Schwartz, T. W., Smit, M. J. and Leurs, R. (2005) CC and CX3C chemokines differentially interact with the N terminus of the human cytomegalovirus-encoded US28 receptor. J. Biol. Chem. 280, 3275-3285. https://doi.org/10.1074/jbc.M407536200
  15. Chee, M. S., Bankier, A. T., Beck, S., Bohni, R., Brown, C. M., Cerny, R., Horsnell, T., Hutchison, C. A., 3rd, Kouzarides, T., Martignetti, J. A., Preddie, E. P., Satchwell, S. C., Tomlinson, P., Weston, K. M. and Barrell, B. G. (1990) Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD169. Curr. Top. Microbiol. Immunol. 154, 125-169.
  16. Fraile-Ramos, A., Kledal, T. N., Pelchen-Matthews, A., Bowers, K., Schwartz, T. W. and Marsh, M. (2001) The human cytomegalovirus US28 protein is located in endocytic vesicles and undergoes constitutive endocytosis and recycling. Mol. Biol. Cell 12, 1737-1749. https://doi.org/10.1091/mbc.12.6.1737
  17. Frostegard, J. (2013) Immunity, atherosclerosis and cardiovascular disease. BMC Med. 11, 117. https://doi.org/10.1186/1741-7015-11-117
  18. Gao, J. L. and Murphy, P. M. (1994) Human cytomegalovirus open reading frame US28 encodes a functional ${\beta}$ chemokine receptor. J. Biol. Chem. 269, 28539-28542.
  19. Hulshof, J. W., Casarosa, P., Menge, W. M., Kuusisto, L. M., van der Goot, H., Smit, M. J., de Esch, I. J. and Leurs, R. (2005) Synthesis and structure-activity relationship of the first nonpeptidergic inverse agonists for the human cytomegalovirus encoded chemokine receptor US28. J. Med. Chem. 48, 6461-6471. https://doi.org/10.1021/jm050418d
  20. Hulshof, J. W., Vischer, H. F., Verheij, M. H., Fratantoni, S. A., Smit, M. J., de Esch, I. J. and Leurs, R. (2006) Synthesis and pharmacological characterization of novel inverse agonists acting on the viral-encoded chemokine receptor US28. Bioorg. Med. Chem. 14, 7213-7230. https://doi.org/10.1016/j.bmc.2006.06.054
  21. Kenneson, A. and Cannon, M. J. (2007) Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev. Med. Virol. 17, 253-276. https://doi.org/10.1002/rmv.535
  22. Kolar, G. R., Grote, S. M. and Yosten, G. L. (2016) Targeting orphan G protein-coupled receptors for the treatment of diabetes and its complications: C-peptide and GPR146. J. Intern. Med. [Epub ahead of print].
  23. Kralj, A., Kurt, E., Tschammer, N. and Heinrich, M. R. (2014) Synthesis and biological evaluation of biphenyl amides that modulate the US28 receptor. ChemMedChem 9, 151-168. https://doi.org/10.1002/cmdc.201300369
  24. Kralj, A., Nguyen, M. T., Tschammer, N., Ocampo, N., Gesiotto, Q., Heinrich, M. R. and Phanstiel, O., 4th. (2013) Development of flavonoid-based inverse agonists of the key signaling receptor US28 of human cytomegalovirus. J. Med. Chem. 56, 5019-5032. https://doi.org/10.1021/jm4003457
  25. Kralj, A., Wetzel, A., Mahmoudian, S., Stamminger, T., Tschammer, N. and Heinrich, M. R. (2011) Identification of novel allosteric modulators for the G-protein coupled US28 receptor of human cytomegalovirus. Bioorg. Med. Chem. Lett. 21, 5446-5450. https://doi.org/10.1016/j.bmcl.2011.06.120
  26. Krupnick, J. G. and Benovic, J. L. (1998) The role of receptor kinases and arrestins in G protein-coupled receptor regulation. Annu. Rev. Pharmacol. Toxicol. 38, 289-319. https://doi.org/10.1146/annurev.pharmtox.38.1.289
  27. Kuhn, D. E., Beall, C. J. and Kolattukudy, P. E. (1995) The cytomegalovirus US28 protein binds multiple CC chemokines with high affinity. Biochem. Biophys. Res. Commun. 211, 325-330. https://doi.org/10.1006/bbrc.1995.1814
  28. Lefkowitz, R. J. (2007) Seven transmembrane receptors: something old, something new. Acta Physiol. (Oxf.) 190, 9-19. https://doi.org/10.1111/j.1365-201X.2007.01693.x
  29. Margulies, B. J., Browne, H. and Gibson, W. (1996) Identification of the human cytomegalovirus G protein-coupled receptor homologue encoded by UL33 in infected cells and enveloped virus particles. Virology 225, 111-125. https://doi.org/10.1006/viro.1996.0579
  30. Maussang, D., Langemeijer, E., Fitzsimons, C. P., Stigter-van Walsum, M., Dijkman, R., Borg, M. K., Slinger, E., Schreiber, A., Michel, D., Tensen, C. P., van Dongen, G. A., Leurs, R. and Smit, M. J. (2009a) The human cytomegalovirus-encoded chemokine receptor US28 promotes angiogenesis and tumor formation via cyclooxygenase-2. Cancer Res. 69, 2861-2869. https://doi.org/10.1158/0008-5472.CAN-08-2487
  31. Maussang, D., Verzijl, D., van Walsum, M., Leurs, R., Holl, J., Pleskoff, O., Michel, D., van Dongen, G. A. and Smit, M. J. (2006) Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis. Proc. Natl. Acad. Sci. U.S.A. 103, 13068-13073. https://doi.org/10.1073/pnas.0604433103
  32. Maussang, D., Vischer, H. F., Schreiber, A., Michel, D. and Smit, M. J. (2009b) Pharmacological and biochemical characterization of human cytomegalovirus-encoded G protein-coupled receptors. Methods Enzymol. 460, 151-171.
  33. Melnychuk, R. M., Streblow, D. N., Smith, P. P., Hirsch, A. J., Pancheva, D. and Nelson, J. A. (2004) Human cytomegalovirus-encoded G protein-coupled receptor US28 mediates smooth muscle cell migration through $G{\alpha}12$. J. Virol. 78, 8382-8391. https://doi.org/10.1128/JVI.78.15.8382-8391.2004
  34. Miller, W. E., Houtz, D. A., Nelson, C. D., Kolattukudy, P. E. and Lefkowitz, R. J. (2003) G-protein-coupled receptor (GPCR) kinase phosphorylation and ${\beta}$-arrestin recruitment regulate the constitutive signaling activity of the human cytomegalovirus US28 GPCR. J. Biol. Chem. 278, 21663-21671. https://doi.org/10.1074/jbc.M303219200
  35. Mokros, T., Rehm, A., Droese, J., Oppermann, M., Lipp, M. and Hopken, U. E. (2002) Surface expression and endocytosis of the human cytomegalovirus-encoded chemokine receptor US28 is regulated by agonist-independent phosphorylation. J. Biol. Chem. 277, 45122-45128. https://doi.org/10.1074/jbc.M208214200
  36. Molleskov-Jensen, A. S., Oliveira, M. T., Farrell, H. E. and Davis-Poynter, N. (2015) Virus-encoded 7 transmembrane receptors. Prog. Mol. Biol. Transl. Sci. 129, 353-393.
  37. Montaner, S., Kufareva, I., Abagyan, R. and Gutkind, J. S. (2013) Molecular mechanisms deployed by virally encoded G protein-coupled receptors in human diseases. Annu. Rev. Pharmacol. Toxicol. 53, 331-354. https://doi.org/10.1146/annurev-pharmtox-010510-100608
  38. Monteclaro, F. S. and Charo, I. F. (1996) The amino-terminal extracellular domain of the MCP-1 receptor, but not the RANTES/MIP-$1{\alpha}$ receptor, confers chemokine selectivity. Evidence for a two-step mechanism for MCP-1 receptor activation. J. Biol. Chem. 271, 19084-19092. https://doi.org/10.1074/jbc.271.32.19084
  39. Murphy, P. M., Baggiolini, M., Charo, I. F., Hebert, C. A., Horuk, R., Matsushima, K., Miller, L. H., Oppenheim, J. J. and Power, C. A. (2000) International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol. Rev. 52, 145-176.
  40. Randolph-Habecker, J. R., Rahill, B., Torok-Storb, B., Vieira, J., Kolattukudy, P. E., Rovin, B. H. and Sedmak, D. D. (2002) The expression of the cytomegalovirus chemokine receptor homolog US28 sequesters biologically active CC chemokines and alters IL-8 production. Cytokine 19, 37-46. https://doi.org/10.1006/cyto.2002.0874
  41. Rosenfeld, M. E. and Campbell, L. A. (2011) Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis. Thromb. Haemost. 106, 858-867. https://doi.org/10.1160/TH11-06-0392
  42. Rosenkilde, M. M., Kledal, T. N., Holst, P. J. and Schwartz, T. W. (2000) Selective elimination of high constitutive activity or chemokine binding in the human herpesvirus 8 encoded seven transmembrane oncogene ORF74. J. Biol. Chem. 275, 26309-26315. https://doi.org/10.1074/jbc.M003800200
  43. Sherrill, J. D. and Miller, W. E. (2006) G protein-coupled receptor (GPCR) kinase 2 regulates agonist-independent Gq/11 signaling from the mouse cytomegalovirus GPCR M33. J. Biol. Chem. 281, 39796-39805. https://doi.org/10.1074/jbc.M610026200
  44. Slinger, E., Langemeijer, E., Siderius, M., Vischer, H. F. and Smit, M. J. (2011) Herpesvirus-encoded GPCRs rewire cellular signaling. Mol. Cell. Endocrinol. 331, 179-184. https://doi.org/10.1016/j.mce.2010.04.007
  45. Slinger, E., Maussang, D., Schreiber, A., Siderius, M., Rahbar, A., Fraile-Ramos, A., Lira, S. A., Soderberg-Naucler, C. and Smit, M. J. (2010) HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6-STAT3 axis. Sci. Signal. 3, ra58.
  46. Soderberg-Naucler, C., Rahbar, A. and Stragliotto, G. (2013) Survival in patients with glioblastoma receiving valganciclovir. N. Engl. J. Med. 369, 985-986. https://doi.org/10.1056/NEJMc1302145
  47. Soroceanu, L., Matlaf, L., Bezrookove, V., Harkins, L., Martinez, R., Greene, M., Soteropoulos, P. and Cobbs, C. S. (2011) Human cytomegalovirus US28 found in glioblastoma promotes an invasive and angiogenic phenotype. Cancer Res. 71, 6643-6653. https://doi.org/10.1158/0008-5472.CAN-11-0744
  48. Streblow, D. N., Soderberg-Naucler, C., Vieira, J., Smith, P., Wakabayashi, E., Ruchti, F., Mattison, K., Altschuler, Y. and Nelson, J. A. (1999) The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration. Cell 99, 511-520. https://doi.org/10.1016/S0092-8674(00)81539-1
  49. Streblow, D. N., Vomaske, J., Smith, P., Melnychuk, R., Hall, L., Pancheva, D., Smit, M., Casarosa, P., Schlaepfer, D. D. and Nelson, J. A. (2003) Human cytomegalovirus chemokine receptor US28-induced smooth muscle cell migration is mediated by focal adhesion kinase and Src. J. Biol. Chem. 278, 50456-50465. https://doi.org/10.1074/jbc.M307936200
  50. Tschammer, N. (2014) Allosteric modulation of the G protein-coupled US28 receptor of human cytomegalovirus: are the small-weight inverse agonist of US28 'camouflaged' agonists? Bioorg. Med. Chem. Lett. 24, 3744-3747. https://doi.org/10.1016/j.bmcl.2014.06.082
  51. Tschische, P., Moser, E., Thompson, D., Vischer, H. F., Parzmair, G. P., Pommer, V., Platzer, W., Schwarzbraun, T., Schaider, H., Smit, M. J., Martini, L., Whistler, J. L. and Waldhoer, M. (2010) The G-protein coupled receptor associated sorting protein GASP-1 regulates the signalling and trafficking of the viral chemokine receptor US28. Traffic 11, 660-674. https://doi.org/10.1111/j.1600-0854.2010.01045.x
  52. Urban, J. D., Clarke, W. P., von Zastrow, M., Nichols, D. E., Kobilka, B., Weinstein, H., Javitch, J. A., Roth, B. L., Christopoulos, A., Sexton, P. M., Miller, K. J., Spedding, M. and Mailman, R. B. (2007) Functional selectivity and classical concepts of quantitative pharmacology. J. Pharmacol. Exp. Ther. 320, 1-13.
  53. Violin, J. D., Ren, X. R. and Lefkowitz, R. J. (2006) G-protein-coupled receptor kinase specificity for ${\beta}$-arrestin recruitment to the ${\beta}_2$-adrenergic receptor revealed by fluorescence resonance energy transfer. J. Biol. Chem. 281, 20577-20588. https://doi.org/10.1074/jbc.M513605200
  54. Vischer, H. F., Hulshof, J. W., Hulscher, S., Fratantoni, S. A., Verheij, M. H., Victorina, J., Smit, M. J., de Esch, I. J. and Leurs, R. (2010) Identification of novel allosteric nonpeptidergic inhibitors of the human cytomegalovirus-encoded chemokine receptor US28. Bioorg. Med. Chem. 18, 675-688. https://doi.org/10.1016/j.bmc.2009.11.060
  55. Vischer, H. F., Siderius, M., Leurs, R. and Smit, M. J. (2014) Herpesvirus-encoded GPCRs: neglected players in inflammatory and proliferative diseases? Nat. Rev. Drug Discov. 13, 123-139. https://doi.org/10.1038/nrd4189
  56. Vomaske, J., Nelson, J. A. and Streblow, D. N. (2009) Human Cytomegalovirus US28: a functionally selective chemokine binding receptor. Infect. Disord. Drug Targets 9, 548-556. https://doi.org/10.2174/187152609789105696
  57. Waldhoer, M., Casarosa, P., Rosenkilde, M. M., Smit, M. J., Leurs, R., Whistler, J. L. and Schwartz, T. W. (2003) The carboxyl terminus of human cytomegalovirus-encoded 7 transmembrane receptor US28 camouflages agonism by mediating constitutive endocytosis. J. Biol. Chem. 278, 19473-19482. https://doi.org/10.1074/jbc.M213179200
  58. Waldhoer, M., Kledal, T. N., Farrell, H. and Schwartz, T. W. (2002) Murine cytomegalovirus (CMV) M33 and human CMV US28 receptors exhibit similar constitutive signaling activities. J. Virol. 76, 8161-8168. https://doi.org/10.1128/JVI.76.16.8161-8168.2002
  59. Zhang, J., Feng, H., Xu, S. and Feng, P. (2016) Hijacking GPCRs by viral pathogens and tumor. Biochem. Pharmacol. 114, 69-81. https://doi.org/10.1016/j.bcp.2016.03.021
  60. Zhang, J., He, S., Wang, Y., Brulois, K., Lan, K., Jung, J. U. and Feng, P. (2015) Herpesviral G protein-coupled receptors activate NFAT to induce tumor formation via inhibiting the SERCA calcium ATPase. PLoS Pathog. 11, e1004768. https://doi.org/10.1371/journal.ppat.1004768

Cited by

  1. Conceptual Progress for the Improvements in the Selectivity and Efficacy of G Protein-Coupled Receptor Therapeutics: An Overview vol.25, pp.1, 2017, https://doi.org/10.4062/biomolther.2016.262
  2. Cyclophilin A as a target in the treatment of cytomegalovirus infections vol.26, pp.2040-2066, 2018, https://doi.org/10.1177/2040206618811413
  3. US28: HCMV’s Swiss Army Knife vol.10, pp.8, 2018, https://doi.org/10.3390/v10080445
  4. HCMV latency: what regulates the regulators? pp.1432-1831, 2019, https://doi.org/10.1007/s00430-019-00581-1
  5. Modulation of Innate Immune Signaling Pathways by Herpesviruses vol.11, pp.6, 2017, https://doi.org/10.3390/v11060572
  6. A comprehensive review on the antiviral activities of chalcones vol.29, pp.4, 2021, https://doi.org/10.1080/1061186x.2020.1853759
  7. Molecular Properties and Therapeutic Targeting of the EBV-Encoded Receptor BILF1 vol.13, pp.16, 2017, https://doi.org/10.3390/cancers13164079