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Viruses 2013

The p36 Isoform of Murine Cytomegalovirus m152 Protein Suffices for Mediating Innate and Adaptive Immune Evasion

DOI: 10.3390/v5123171

Annette Fink,Angeliqué Renzaho,Matthias J. Reddehase,Niels A. W. Lemmermann

Keywords: antigen presentation, BAC mutagenesis, CD8 T cells, cytomegalovirus, viral immune evasion, natural killer (NK) cells, N-linked glycosylation

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Abstract:

The MHC-class I (MHC-I)-like viral (MHC-Iv) m152 gene product of murine cytomegalovirus (mCMV) was the first immune evasion molecule described for a member of the β-subfamily of herpesviruses as a paradigm for analogous functions of human cytomegalovirus proteins. Notably, by interacting with classical MHC-I molecules and with MHC-I-like RAE1 family ligands of the activatory natural killer (NK) cell receptor NKG2D, it inhibits presentation of antigenic peptides to CD8 T cells and the NKG2D-dependent activation of NK cells, respectively, thus simultaneously interfering with adaptive and innate immune recognition of infected cells. Although the m152 gene product exists in differentially glycosylated isoforms whose individual contributions to immune evasion are unknown, it has entered the scientific literature as m152/gp40, based on the quantitatively most prominent isoform but with no functional justification. By construction of a recombinant mCMV in which all three N-glycosylation sites are mutated (N61Q, N208Q, and N241Q), we show here that N-linked glycosylation is not essential for functional interaction of the m152 immune evasion protein with either MHC-I or RAE1. These data add an important functional detail to recent structural analysis of the m152/RAE1g complex that has revealed N-glycosylations at positions Asn61 and Asn208 of m152 distant from the m152/RAE1g interface.

References

[1]	Krmpotic, A.; Hasan, M.; Loewendorf, A.; Saulig, T.; Halenius, A.; Lenac, T.; Polic, B.; Bubic, I.; Kriegeskorte, A.; Pernjak-Pugel, E.; et al. NK cell activation through the NKG2D ligand MULT-1 is selectively prevented by the glycoprotein encoded by mouse cytomegalovirus gene m145. J. Exp. Med. 2005, 201, 211–220, doi:10.1084/jem.20041617.
[2]	Lodoen, M.; Ogasawara, K.; Hamerman, J.; Arase, H.; Houchins, J.; Mocarski, E.; Lanier, L. NKG2D-mediated natural killer cell protection against cytomegalovirus is impaired by viral gp40 modulation of retinoic acid early inducible 1 gene molecules. J. Exp. Med. 2003, 197, 1245–1253, doi:10.1084/jem.20021973.
[3]	Lodoen, M.; Abenes, G.; Umamoto, S.; Houchins, J.; Liu, F.; Lanier, L. The cytomegalovirus m155 gene product subverts natural killer cell antiviral protection by disruption of H60-NKG2D interactions. J. Exp. Med. 2004, 200, 1075–1081.
[4]	Hasan, M.; Krmpotic, A.; Ruzsics, Z.; Bubic, I.; Lenac, T.; Halenius, A.; Loewendorf, A.; Messerle, M.; Hengel, H.; Jonjic, S.; et al. Selective down-regulation of the NKG2D ligand H60 by mouse cytomegalovirus m155 glycoprotein. J. Virol. 2005, 79, 2920–2930, doi:10.1128/JVI.79.5.2920-2930.2005.
[5]	Jonji？, S.; Babi？, M.; Poli？, B.; Krmpoti？, A. Immune evasion of natural killer cells by viruses. Curr. Opin. Immunol. 2008, 20, 30–38, doi:10.1016/j.coi.2007.11.002.
[6]	Lenac, T.; Arapovi？, J.; Traven, L.; Krmpoti？, A.; Jonji？, S. Murine cytomegalovirus regulation of NKG2D ligands. Med. Microbiol. Immunol. 2008, 197, 159–166, doi:10.1007/s00430-008-0080-7.
[7]	Lisni？, V.J.; Krmpoti？, A.; Jonji？, S. Modulation of natural killer cell activity by viruses. Curr. Opin. Microbiol. 2010, 13, 530–539, doi:10.1016/j.mib.2010.05.011.
[8]	Slavuljica, I.; Krmpoti？, A.; Jonji？, S. Manipulation of NKG2D ligands by cytomegaloviruses: Impact on innate and adaptive immune response. Front. Immunol. 2011, 2, doi:10.3389/fimmu.2011.00085.
[9]	Vidal, S.; Krmpoti？, A.; Pyzik, M.; Jonji？, S. Innate immunity to cytomegalovirus in the murine model. In Cytomegaloviruses: From Molecular Pathogenesis to Intervention; Reddehase, M.J., Ed.; Caister Academic Press: Wymondham, Norfolk, UK, 2013; pp. 191–213.
[10]	Th？le, R.; Szepan, U.; Hengel, H.; Geginat, G.; Lucin, P.; Koszinowski, U.H. Identification of the mouse cytomegalovirus genomic region affecting major histocompatibility complex class I molecule transport. J. Virol. 1995, 69, 6098–6105.
[11]	Del Val, M.; Hengel, H.; H？cker, H.; Hartlaub, U.; Ruppert, T.; Lucin, P.; Koszinowski, U. Cytomegalovirus prevents antigen presentation by blocking the transport of peptide-loaded major histocompatibility complex class I molecules into the medial-Golgi compartment. J. Exp. Med. 1992, 176, 729–738, doi:10.1084/jem.176.3.729.
[12]	Ziegler, H.; Th？le, R.; Lucin, P.; Muranyi, W.; Flohr, T.; Hengel, H.; Farrell, H.; Rawlinson, W.; Koszinowski, U. A mouse cytomegalovirus glycoprotein retains MHC Class I complexes in the ERGIC/ cis-Golgi compartments. Immunity 1997, 6, 57–66, doi:10.1016/S1074-7613(00)80242-3.
[13]	Krmpotic, A.; Messerle, M.; Crnkovic-Mertens, I.; Polic, B.; Jonjic, S.; Koszinowski, U. The immunoevasive function encoded by the mouse cytomegalovirus gene m152 protects the virus against T cell control in vivo. J. Exp. Med. 1999, 190, 1285–1296, doi:10.1084/jem.190.9.1285.
[14]	Krmpoti？, A.; Busch, D.H.; Bubi？, I.; Gebhardt, F.; Hengel, H.; Hasan, M.; Scalzo, A.A.; Koszinowski, U.H.; Jonji？, S. MCMV glycoprotein gp40 confers virus resistance to CD8+ T cells and NK cells in vivo. Nat. Immunol. 2002, 3, 529–535, doi:10.1038/ni799.
[15]	Holtappels, R.; Podlech, J.; Pahl-Seibert, M.; Jülch, M.; Thomas, D.; Simon, C.O.; Wagner, M.; Reddehase, M.J. Cytomegalovirus misleads its host by priming of CD8 T cells specific for an epitope not presented in infected tissues. J. Exp. Med. 2004, 199, 131–136.
[16]	Reddehase, M.J. Antigens and immunoevasins: Opponents in cytomegalovirus immune surveillance. Nat. Rev. Immunol. 2002, 2, 831–844, doi:10.1038/nri932.
[17]	Lemmermann, N.A.; B？hm, V.; Holtappels, R.; Reddehase, M.J. In vivo impact of cytomegalovirus evasion of CD8 T-cell immunity: Facts and thoughts based on murine models. Virus Res. 2011, 157, 161–174, doi:10.1016/j.virusres.2010.09.022.
[18]	Lemmermann, N.A.; Fink, A.; Podlech, J.; Ebert, S.; Wilhelmi, V.; B？hm, V.; Holtappels, R.; Reddehase, M.J. Murine cytomegalovirus immune evasion proteins operative in the MHC class I pathway of antigen processing and presentation: State of knowledge, revisions, and questions. Med. Microbiol. Immunol. 2012, 201, 497–512, doi:10.1007/s00430-012-0257-y.
[19]	Hansen, T.H.; Bouvier, M. MHC class I antigen presentation: Learning from viral evasion strategies. Nat. Rev. Immunol. 2009, 9, 503–513, doi:10.1038/nri2575.
[20]	Lemmermann, N.A.; Gergely, K.; B？hm, V.; Deegen, P.; D？ubner, T.; Reddehase, M.J. Immune evasion proteins of murine cytomegalovirus preferentially affect cell surface display of recently generated peptide presentation complexes. J. Virol. 2010, 84, 1221–1236, doi:10.1128/JVI.02087-09.
[21]	Ziegler, H.; Muranyi, W.; Burgert, H.; Kremmer, E.; Koszinowski, U. The luminal part of the murine cytomegalovirus glycoprotein gp40 catalyzes the retention of MHC class I molecules. EMBO J. 2000, 19, 870–881, doi:10.1093/emboj/19.5.870.
[22]	Zhi, L.; Mans, J.; Paskow, M.J.; Brown, P.H.; Schuck, P.; Jonji？, S.; Natarajan, K.; Margulies, D.H. Direct interaction of the mouse cytomegalovirus m152/gp40 immunoevasin with RAE-1 isoforms. Biochemistry 2010, 49, 2443–2453, doi:10.1021/bi902130j.
[23]	Arapovic, J.; Lenac, T.; Antulov, R.; Polic, B.; Ruzsics, Z.; Carayannopoulos, L.N.; Koszinowski, U.H.; Krmpotic, A.; Jonjic, S. Differential susceptibility of RAE-1 isoforms to mouse cytomegalovirus. J. Virol. 2009, 83, 8198–8207, doi:10.1128/JVI.02549-08.
[24]	Wang, R.; Natarajan, K.; Revilleza, M.; Boyd, L.; Zhi, L.; Zhao, H.; Robinson, H.; Margulies, D. Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion. Proc. Natl. Acad. Sci. USA 2012, 109, 3578–3587, doi:10.1073/pnas.1214088109.
[25]	Reusch, U.; Muranyi, W.; Lucin, P.; Burgert, H.G.; Hengel, H.; Koszinowski, U.H. A cytomegalovirus glycoprotein re-routes MHC class I complexes to lysosomes for degradation. EMBO J. 1999, 18, 1081–1091, doi:10.1093/emboj/18.4.1081.
[26]	Fink, A.; Lemmermann, N.A.; Gillert-Marien, D.; Thomas, D.; Freitag, K.; B？hm, V.; Wilhelmi, V.; Reifenberg, K.; Reddehase, M.J.; Holtappels, R. Antigen presentation under the influence of “immune evasion” proteins and its modulation by interferon-gamma: Implications for immunotherapy of cytomegalovirus infection with antiviral CD8 T cells. Med. Microbiol. Immunol. 2012, 201, 513–525, doi:10.1007/s00430-012-0256-z.
[27]	Wagner, M.; Gutermann, A.; Podlech, J.; Reddehase, M.J.; Koszinowski, U.H. Major histocompatibility complex class I allele-specific cooperative and competitive interactions between immune evasion proteins of cytomegalovirus. J. Exp. Med. 2002, 196, 805–816, doi:10.1084/jem.20020811.
[28]	Kleijnen, M.; Huppa, J.; Lucin, P.; Mukherjee, S.; Farrell, H.; Campbell, A.; Koszinowski, U.H.; Hill, A.; Ploegh, H. A mouse cytomegalovirus glycoprotein, gp34, forms a complex with folded class I MHC molecules in the ER which is not retained but is transported to the cell surface. EMBO J. 1997, 16, 685–694, doi:10.1093/emboj/16.4.685.
[29]	D？ubner, T.; Fink, A.; Seitz, A.; Tenzer, S.; Müller, J.; Strand, D.; Seckert, C.K.; Janssen, C.; Renzaho, A.; Grzimek, N.K.; et al. A novel transmembrane domain mediating retention of a highly motile herpesvirus glycoprotein in the endoplasmic reticulum. J. Gen. Virol. 2010, 91, 1524–1534, doi:10.1099/vir.0.018580-0.
[30]	Holtappels, R.; Gillert-Marien, D.; Thomas, D.; Podlech, J.; Deegen, P.; Herter, S.; Oehrlein-Karpi, S.; Strand, D.; Wagner, M.; Reddehase, M.J. Cytomegalovirus encodes a positive regulator of antigen presentation. J. Virol. 2006, 80, 7613–7624, doi:10.1128/JVI.00723-06.
[31]	Angulo, A.; Ghazal, P.; Messerle, M. The major immediate-early gene ie3 of mouse cytomegalovirus is essential for viral growth. J. Virol. 2000, 74, 11129–11136, doi:10.1128/JVI.74.23.11129-11136.2000.
[32]	Podlech, J. University Medical Center Mainz: Mainz, Germany, 2013.
[33]	Erlach, K.C.; B？hm, V.; Knabe, M.; Deegen, P.; Reddehase, M.J.; Podlech, J. Activation of hepatic natural killer cells and control of liver-adapted lymphoma in the murine model of cytomegalovirus infection. Med. Microbiol. Immunol. 2008, 197, 167–178, doi:10.1007/s00430-008-0084-3.
[34]	Slavuljica, I.; Busche, A.; Babi？, M.; Mitrovi？, M.; Ga？parovi？, I.; Cekinovi？, D.; Markova Car, E.; Pernjak Pugel, E.; Cikovi？, A.; Lisni？, V.J.; et al. Recombinant mouse cytomegalovirus expressing a ligand for the NKG2D receptor is attenuated and has improved vaccine properties. J. Clin. Invest. 2010, 120, 4532–4545, doi:10.1172/JCI43961.
[35]	Rawlinson, W.; Farrell, H.; Barrell, B. Analysis of the complete DNA sequence of murine cytomegalovirus. J. Virol. 1996, 70, 8833–8849.
[36]	Wagner, M.; Jonjic, S.; Koszinowski, U.; Messerle, M. Systematic excision of vector sequences from the BAC-cloned herpesvirus genome during virus reconstitution. J. Virol. 1999, 73, 7056–7060.
[37]	Kurz, S.; Steffens, H.; Mayer, A.; Harris, J.; Reddehase, M. Latency versus persistence or intermittent recurrences: Evidence for a latent state of murine cytomegalovirus in the lungs. J. Virol. 1997, 71, 2980–2987.
[38]	Lemmermann, N.A.; Podlech, J.; Seckert, C.; Kropp, K.; Grzimek, N.K.; Reddehase, M.J.; Holtappels, R. CD8 T-cell immunotherapy of cytomegalovirus disease in the murine model. In Methods in Microbiology; Kabelitz, D., Kaufmann, S., Eds.; Academic Press: London, UK, 2010; pp. 369–420.
[39]	Wolfram Mathematica, version 9, Wolfram Research, Champaign, IL, USA, 2012.
[40]	Ho, E.L.; Carayannopoulos, L.N.; Poursine-Laurent, J.; Kinder, J.; Plougastel, B.; Smith, H.R.; Yokoyama, W.M. Costimulation of multiple NK cell activation receptors by NKG2D. J. Immunol. 2002, 169, 3667–3675.
[41]	B？hm, V.; Simon, C.; Podlech, P.; Seckert, C.; Gendig, D.; Deegen, P.; Gillert-Marien, D.; Lemmermann, N.A.; Holtappels, R.; Reddehase, M.J. The immune evasion paradox: Immunoevasins of murine cytomegalovirus enhance priming of CD8 T cells by preventing negative feedback regulation. J. Virol. 2008, 82, 11637–11650, doi:10.1128/JVI.01510-08.
[42]	CXP Acquisition, version 2.2, Beckman Coulter, Indianapolis, IN, USA, 2006.
[43]	Borst, E.; Posfai, G.; Pogoda, M.; Messerle, M. Mutagenesis of herpesvirus BACs by allele replacement. In Methods Mol. Biol., Bacterial Artificial Chromosomes; Zhao, S., Stodolsky, M., Eds.; Humana Press: Totowa, NJ, USA, 2004; pp. 269–280.
[44]	Tischer, B.; von Einem, J.; Kaufer, B.; Osterrieder, N. Two-step Red-mediated recombination for versatile high-efficiency markerless DNA manipulation in Escherichia coli. Biotechniques 2006, 40, 191–197, doi:10.2144/000112096.
[45]	Warming, S.; Costantino, N.; Court, D.; Jenkins, N.; Copeland, G. Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Res. 2005, 33, e36, doi:10.1093/nar/gni035.

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