Abstract
The Us3 kinase is part of the antiapoptotic arsenal that salvages herpes simplex virus (HSV)-1-infected cells from damage caused by different stimuli. We demonstrate that Us3 protects HSV-1-infected cells from lysis by MHC class I-restricted CD8T cells without affecting antigen presentation. Expression of Us3 was associated with inhibition of caspase activation and reduced cleavage of the proapoptotic protein Bid. Recombinant granzyme B (GrB) failed to cleave Bid in cytosolic extracts from Us3 positive cells, while recombinant Bid served as substrate for Us3 phosphorylation, suggesting that modification of Bid by Us3 blocks its processing by GrB. Our data illustrate a new strategy of viral escape, where modification of a cellular proapoptotic substrate may prevent lysis of the infected cells without affecting other T-cell functions.
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Abbreviations
- HSV:
-
herpes simplex virus
- Us3:
-
unique short 3
- GrB:
-
granzyme B
- CTL:
-
cytotoxic T cell
- LCL:
-
lymphoblastoid cell line
- MHC:
-
major histocompatibility complex
References
Nash AA (2000) T cells and the regulation of herpes simplex virus latency and reactivation. J. Exp. Med. 191: 1455–1457
Cunningham AL, Mindel A and Dwyer DE (2000) Global epidemiology of sexually transmitted disease. In Sexually Transmitted Diseases Standberry L and Bernstein D (eds) (San Diego: Academic Press), pp. 3–42
Dahershia M, Feldman LT and Rouse BT (1998) Herpes virus latency and the immune response. Curr. Opin. Microbiol. 1: 430–435
Simmons A and Tscharke DC (1992) Anti-CD8 impairs clearance of herpes simplex virus from the nervous system: implication for the fate of virally infected neurons. J. Exp. Med. 175: 1337–1344
Shimeld C, Whiteland JL, Nicholls SM, Grinfeld E, Easty DL, Gao H and Hill TJ (1995) Immune cell infiltration and persistence in the mouse trigeminal ganglion after infection of the cornea with herpes simplex type-1. J. Neuroimmunol. 61: 7–16
Liu T, Khanna KM, Chen X, Fink DJ and Hendrix RL (2000) CD81T cells can block herpes simplex virus type 1 (HSV-1) reactivation from latency in sensory neurons. J. Exp. Med. 191: 1459–1466
Kagi D, Ledermann B, Burki K, Zinkernagel RM and Hengartner H (1996) Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. Ann. Rev. Immunol. 14: 207–232
Atkinson EA and Bleackley RC (1995) Mechanisms of lysis by cytotoxic T cells. Crit. Rev. Immunol. 15: 359–384
Darmon AJ, Nicholson DW and Bleackley RC (1995) Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B. Nature 377: 446–448
Darmon AJ, Ley TJ, Nicholson DW and Bleackley RC (1996) Cleavage of CPP32 by granzyme B represents a critical role for granzyme B in the induction of target cell DNA fragmentation. J. Biol. Chem. 271: 21709–21712
Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M and Lazebnik YA (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376: 37–43
Tewari M, Quan LT, O'Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirier GG, Salvesen GS and Dixit VM (1995) Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 81: 801–809
Jerome KR, Tait JF, Koelle DM and Corey L (1998) Herpes simplex virus type 1 renders infected cells resistant to cytotoxic T-lymphocyte-induced apoptosis. J. Virol. 72: 436–441
Jerome KR, Fox R, Chen Z, Sears AE, Lee H and Corey L (1999) Herpes simplex virus inhibits apoptosis through the action of two genes, Us5 and Us3. J. Virol. 73: 8950–8957
Jerome KR, Chen Z, Lang R, Torres MR, Hofmeister J, Smith S, Fox R, Froelich CJ and Corey L (2001) HSV and glycoprotein J inhibit caspase activation and apoptosis induced by granzyme B or Fas. J. Immunol. 167: 3928–3935
Purves FC, Longnecker RM, Leader DP and Roizman B (1987) Herpes simplex virus 1 protein kinase is encoded by open reading frame US3 which is not essential for virus growth in cell culture. J. Virol. 61: 2896–2901
Munger J and Roizman B (2001) The US3 protein kinase of herpes simplex virus 1 mediates the posttranslational modification of BAD and prevents BAD-induced programmed cell death in the absence of other viral proteins. Proc. Natl. Acad. Sci. USA 98: 10410–10415
Tortorella D, Gewurs BE, Furman MH, Schust DJ and Ploegh HL (2000) Viral subversion of the immune system. Ann. Rev. Immunol. 18: 861–926
Sutton VR, Davis JE, Cancilla M, Johnstone RW, Ruefli AA, Sedelies K, Browne KA and Trapani JA (2000) Initiation of apoptosis by granzyme B requires direct cleavage of Bid, but not direct granzyme B-mediated caspase activation. J. Exp. Med. 192: 1403–1414
Desagher S, Osen-Sand A, Montessuit S, Magnenat E, Vilbois F, Hochmann A, Journot L, Antonsson B and Martinou JC (2001) Phosphorylation of Bid by casein kinases I and II regulates its cleavage by caspase 8. Mol. Cell 8: 601–611
Frame MC, Purves FC, McGeoch DJ, Marsden HS and Leader DP (1987) Identification of the herpes simplex virus protein kinase as the product of viral gene US3. J. Gen. Virol. 68: 2699–2704
Heibein JA, Swie Goping I, Barry M, Pinkoski MJ, Shore GC and Green DR (2000) Granzyme-B-mediated cytochrome c release is regulated by the Bcl-2 family members Bid and Max. J. Exp. Med. 192: 1391–1401
Thomas DA, Scorrano L, Putcha GV, Korsmeyer SJ and Ley TJ (2001) Granzyme B can cause mitochondrial depolarization and cell death in the absence of BID, BAX, and BAK. Proc. Natl. Acad. Sci. USA 98: 14985–14990
Cartier A, Komai T and Masucci MG (2003) The Us3 protein kinase of Herpes simplex virus-1 block apoptosis by inducing phosphorylation of the Bcl2 family member Bad. Exp. Cell Res. in press
Hill A, Jugovic P, York I, Russ G, Bennink J, Yewdell J, Ploegh H and Johnson D (1995) Herpes simplex virus turns off the TAP to evade host immunity. Nature 375: 411–415
Cunningham AL, Turner RR, Meiller AC, Para MF and Merigan TC (1985) Evolution of recurrent herpes simplex virus lesions. J. Clin. Invest. 75: 226–233
Nishiyama Y, Yamada Y, Kurachi R and Daikoku T (1992) Construction of a US3 lacZ insertion mutant of herpes simplex virus type 2 and characterization of its phenotype in vitro and in vivo. Virology 190: 256–268
Meignier B, Longnecker R, Mavromara-Nazos P, Sears AE and Roizman B (1988) Virulence of and establishment of latency by genetically engineered deletion mutants of herpes simplex virus 1. Virology 162: 251–254
Yamamoto M, Kurachi R, Morishima T, Kito J and Nishiyama Y (1996) Immunohistochemical studies on the transneuronal spread of virulent herpes simplex virus type 2 and its US3 protein kinase-deficient mutant after ocular inoculation. Microbiol. Immunol. 40: 289–294
Barnstable CJ, Bodmer WF, Brown G, Galfre G, Milstein C, Williams AF and Ziegler A (1978) Production of monoclonal antibodies to group A erythrocytes, HLA and other human cell surface antigens – new tools for genetic analysis. Cell 14: 9–20
Wang K, Yin XM, Chao DT, Milliman CL and Korsmeyer SJ (1996) BID: a novel BH3 domain-only death agonist. Genes Dev. 10: 2859–2869
Miller G and Lipman M (1973) Release of infectious Epstein–Barr virus by transformed marmoset leukocytes. Proc. Natl. Acad. Sci. USA 70: 190–194
Ejercito PM, Kieff ED and Roizman B (1968) Characterization of herpes simplex virus strains differing in their effects on social behavior of infected cells. J. Gen. Virol. 2: 357–364
Torsteinsdottir S, Masucci MG, Ehlin-Henriksson B, Brautbar C, Ben Bassat H, Klein G and Klein E (1986) Differentiation-dependent sensitivity of human B-cell-derived lines to major histocompatibility complex-restricted T-cell cytotoxicity. Proc. Natl. Acad. Sci. USA 83: 5620–5624
Neefjes JJ, Breur-Vriesendorp BS, van Seventer GA, Ivanyi P and Ploegh HL (1986) An improved biochemical method for the analysis of HLA-class I antigens. Definition of new HLA-class I subtypes. Human Immunol. 16: 169–181
Wei CH, Yagita H, Masucci MG and Levitsky V (2001) Different programs of activation-induced cell death are triggered in mature activated CTL by immunogenic and partially agonistic peptide ligands. J. Immunol. 166: 989–995
Acknowledgements
We thank B Roizman, A Sharipo and X Wang for the kind gift of HSV-1 strains and specific antibodies and V Levitsky for the gift of EBV-specific cytotoxic T cells. This investigation was supported by grants from the Swedish Cancer Society, the Swedish Foundation for Strategic Research and the Karolinska Institutet, Stockholm, Sweden.
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Cartier, A., Broberg, E., Komai, T. et al. The herpes simplex virus-1 Us3 protein kinase blocks CD8T cell lysis by preventing the cleavage of Bid by granzyme B. Cell Death Differ 10, 1320–1328 (2003). https://doi.org/10.1038/sj.cdd.4401308
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DOI: https://doi.org/10.1038/sj.cdd.4401308
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