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MHC class I antigen presentation: learning from viral evasion strategies

Key Points

  • Viruses and their mammalian hosts have co-evolved for millions of years, resulting in intricate host–pathogen interactions. As a result viruses have evolved several mechanisms to 'hide' from the host immune system.

  • Virus-infected cells are detected by host cytotoxic T cells when the infected cell displays on the surface a virus-derived peptide bound to an MHC class I molecule. This pathway, termed antigen presentation, is a target for viral immune evasion proteins.

  • Antigen presentation involves proteasome-dependent peptide generation in the cytoplasm, TAP-dependent peptide transport into the lumen of the endoplasmic reticulum (ER), where binding to MHC class I molecules occurs, and transit of stable peptide-loaded MHC class I molecules through the secretory pathway to the plasma membrane for T cell recognition.

  • To evade T cell recognition, viruses have evolved elaborate mechanisms to block antigen presentation. The viral immune evasion mechanisms include: inhibition of proteasome function, TAP-mediated peptide transport, chaperone-facilitated peptide loading and transit of MHC class I molecules from the ER.

  • Viruses also co-opt ubiquitin-dependent pathways to remove nascent MHC class I molecules from the ER for proteasome-mediated degradation or induce rapid endocytosis of surface MHC class I molecules for lysosome-mediated degradation. Interestingly, the existence of host proteins with similar structures and functions suggest that the viruses have acquired ancestral homologues from the host, which have evolved for use as immune evasion proteins.

  • The finding that viral immune evasion proteins are potent and highly specific for host protein interactions makes these natural inhibitors effective probes for dissecting physiological pathways.

Abstract

The cell surface display of peptides by MHC class I molecules to lymphocytes provides the host with an important surveillance mechanism to protect against invading pathogens. However, in turn, viruses have evolved elegant strategies to inhibit various stages of the MHC class I antigen presentation pathway and prevent the display of viral peptides. This Review highlights how the elucidation of mechanisms of viral immune evasion is important for advancing our understanding of virus–host interactions and can further our knowledge of the MHC class I presentation pathway as well as other cellular pathways.

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Figure 1: The MHC class I antigen presentation pathway is targeted by viral immune evasion proteins.
Figure 2: Modulation of proteasome and TAP functions by viral immune evasion proteins.
Figure 3: Modulation of tapasin function and retention of MHC class I molecules by viral immune evasion proteins.
Figure 4: Proposed mechanisms for the modulation of MHC class I presentation pathway by herpesvirus proteins.

References

  1. 1

    Purcell, A. W. & Elliott, T. Molecular machinations of the MHC-I peptide loading complex. Curr. Opin. Immunol. 20, 75–81 (2008).

    CAS  Article  Google Scholar 

  2. 2

    Peaper, D. R. & Cresswell, P. Regulation of MHC class I assembly and peptide binding. Annu. Rev. Cell Dev. Biol. 24, 343–368 (2008).

    CAS  Article  Google Scholar 

  3. 3

    Sadegh-Nasseri, S., Chen, M., Narayan, K. & Bouvier, M. The convergent roles of tapasin and HLA-DM in antigen presentation. Trends Immunol. 29, 141–147 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Fruh, K., Gruhler, A., Krishna, R. M. & Schoenhals, G. J. A comparison of viral immune escape strategies targeting the MHC class I assembly pathway. Immunol. Rev. 168, 157–166 (1999).

    CAS  Article  Google Scholar 

  5. 5

    Lilley, B. N. & Ploegh, H. L. Viral modulation of antigen presentation: manipulation of cellular targets in the ER and beyond. Immunol. Rev. 207, 126–144 (2005).

    CAS  Article  Google Scholar 

  6. 6

    Rock, K. L. et al. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell 78, 761–771 (1994).

    CAS  Article  Google Scholar 

  7. 7

    Baumeister, W., Walz, J., Zuhl, F. & Seemuller, E. The proteasome: paradigm of a self-compartmentalizing protease. Cell 92, 367–380 (1998).

    CAS  Article  Google Scholar 

  8. 8

    Levitskaya, J. et al. Inhibition of antigen processing by the internal repeat region of the Epstein–Barr virus nuclear antigen-1. Nature 375, 685–688 (1995).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Dantuma, N. P., Heessen, S., Lindsten, K., Jellne, M. & Masucci, M. G. Inhibition of proteasomal degradation by the Gly-Ala repeat of Epstein–Barr virus is influenced by the length of the repeat and the strength of the degradation signal. Proc. Natl Acad. Sci. USA 97, 8381–8385 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Bennett, N. J., May, J. S. & Stevenson, P. G. Gamma-herpesvirus latency requires T cell evasion during episome maintenance. PLoS Biol. 3, e120 (2005).

    PubMed  PubMed Central  Google Scholar 

  11. 11

    Zaldumbide, A., Ossevoort, M., Wiertz, E. J. & Hoeben, R. C. In cis inhibition of antigen processing by the latency-associated nuclear antigen I of Kaposi sarcoma herpes virus. Mol. Immunol. 44, 1352–1360 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Kwun, H. J. et al. 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. 81, 8225–8235 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Daskalogianni, C. et al. Gly-Ala repeats induce position- and substrate-specific regulation of 26 S proteasome-dependent partial processing. J. Biol. Chem. 283, 30090–30100 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Masucci, M. G. Epstein–Barr virus oncogenesis and the ubiquitin-proteasome system. Oncogene 23, 2107–2115 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Kelly, A. et al. Assembly and function of the two ABC transporter proteins encoded in the human major histocompatibility complex. Nature 355, 641–644 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Schmitt, L. & Tampe, R. Structure and mechanism of ABC transporters. Curr. Opin. Struct. Biol. 12, 754–760 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Fruh, K. et al. A viral inhibitor of peptide transporters for antigen presentation. Nature 375, 415–418 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Hill, A. et al. Herpes simplex virus turns off the TAP to evade host immunity. Nature 375, 411–415 (1995). This study, together with reference 17, identifies the first viral inhibitor of TAP.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Ahn, K. et al. The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP. Immunity 6, 613–621 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Hengel, H. et al. A viral ER-resident glycoprotein inactivates the MHC-encoded peptide transporter. Immunity 6, 623–632 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Lehner, P. J., Karttunen, J. T., Wilkinson, G. W. & Cresswell, P. The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation. Proc. Natl Acad. Sci. USA 94, 6904–6909 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Koppers-Lalic, D. et al. Varicellovirus UL 49.5 proteins differentially affect the function of the transporter associated with antigen processing, TAP. PLoS Pathog. 4, e1000080 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Koppers-Lalic, D. et al. Varicelloviruses avoid T cell recognition by UL49.5-mediated inactivation of the transporter associated with antigen processing. Proc. Natl Acad. Sci. USA 102, 5144–5149 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Hislop, A. D. et al. A CD8+ T cell immune evasion protein specific to Epstein–Barr virus and its close relatives in Old World primates. J. Exp. Med. 204, 1863–1873 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Horst, D. et al. Specific targeting of the EBV lytic phase protein BNLF2a to the transporter associated with antigen processing results in impairment of HLA class I-restricted antigen presentation. J. Immunol. 182, 2313–2324 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Gatfield, J. et al. Cell lines transfected with the TAP inhibitor ICP47 allow testing peptide binding to a variety of HLA class I molecules. Int. Immunol. 10, 1665–1672 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Wei, M. L. & Cresswell, P. HLA-A2 molecules in an antigen-processing mutant cell contain signal sequence-derived peptides. Nature 356, 443–446 (1992).

    CAS  Article  Google Scholar 

  28. 28

    Ahn, K. et al. Molecular mechanism and species specificity of TAP inhibition by herpes simplex virus ICP47. EMBO J. 15, 3247–3255 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Tomazin, R. et al. Stable binding of the herpes simplex virus ICP47 protein to the peptide binding site of TAP. EMBO J. 15, 3256–3266 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Lacaille, V. G. & Androlewicz, M. J. Herpes simplex virus inhibitor ICP47 destabilizes the transporter associated with antigen processing (TAP) heterodimer. J. Biol. Chem. 273, 17386–17390 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Gorbulev, S., Abele, R. & Tampe, R. Allosteric crosstalk between peptide-binding, transport, and ATP hydrolysis of the ABC transporter TAP. Proc. Natl Acad. Sci. USA 98, 3732–3737 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Galocha, B. et al. The active site of ICP47, a herpes simplex virus-encoded inhibitor of the major histocompatibility complex (MHC)-encoded peptide transporter associated with antigen processing (TAP), maps to the NH2-terminal 35 residues. J. Exp. Med. 185, 1565–1572 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Neumann, L., Kraas, W., Uebel, S., Jung, G. & Tampe, R. The active domain of the herpes simplex virus protein ICP47: a potent inhibitor of the transporter associated with antigen processing. J. Mol. Biol. 272, 484–492 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Hewitt, E. W., Gupta, S. S. & Lehner, P. J. The human cytomegalovirus gene product US6 inhibits ATP binding by TAP. EMBO J. 20, 387–396 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Kyritsis, C. et al. Molecular mechanism and structural aspects of transporter associated with antigen processing inhibition by the cytomegalovirus protein US6. J. Biol. Chem. 276, 48031–48039 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Jugovic, P., Hill, A. M., Tomazin, R., Ploegh, H. & Johnson, D. C. Inhibition of major histocompatibility complex class I antigen presentation in pig and primate cells by herpes simplex virus type 1 and 2 ICP47. J. Virol. 72, 5076–5084 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Halenius, A. et al. Physical and functional interactions of the cytomegalovirus US6 glycoprotein with the transporter associated with antigen processing. J. Biol. Chem. 281, 5383–5390 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Loch, S. et al. Signaling of a varicelloviral factor across the endoplasmic reticulum membrane induces destruction of the peptide-loading complex and immune evasion. J. Biol. Chem. 283, 13428–13436 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Verweij, M. C. et al. The varicellovirus UL49.5 protein blocks the transporter associated with antigen processing (TAP) by inhibiting essential conformational transitions in the 6+6 transmembrane TAP core complex. J. Immunol. 181, 4894–4907 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Chen, M., Abele, R. & Tampe, R. Peptides induce ATP hydrolysis at both subunits of the transporter associated with antigen processing. J. Biol. Chem. 278, 29686–29692 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Koch, J., Guntrum, R., Heintke, S., Kyritsis, C. & Tampe, R. Functional dissection of the transmembrane domains of the transporter associated with antigen processing (TAP). J. Biol. Chem. 279, 10142–10147 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Koch, J., Guntrum, R. & Tampe, R. The first N-terminal transmembrane helix of each subunit of the antigenic peptide transporter TAP is essential for independent tapasin binding. FEBS Lett. 580, 4091–4096 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Rufer, E., Leonhardt, R. M. & Knittler, M. R. Molecular architecture of the TAP-associated MHC class I peptide-loading complex. J. Immunol. 179, 5717–5727 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Dong, G., Wearsch, P. A., Peaper, D. R., Cresswell, P. & Reinisch, K. M. Insights into MHC class I peptide loading from the structure of the tapasin–ERp57 thiol oxidoreductase heterodimer. Immunity 30, 21–32 (2009). This study describes the structure of the tapasin–ERp57 interactionand also mapped a putative MHC class I interaction surface in tapasin that is crucial for peptide loading.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Schoenhals, G. J. et al. Retention of empty MHC class I molecules by tapasin is essential to reconstitute antigen presentation in invertebrate cells. EMBO J. 18, 743–753 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Peh, C. A., Laham, N., Burrows, S. R., Zhu, Y. & McCluskey, J. Distinct functions of tapasin revealed by polymorphism in MHC class I peptide loading. J. Immunol. 164, 292–299 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Chen, M. & Bouvier, M. Analysis of interactions in a tapasin/class I complex provides a mechanism for peptide selection. EMBO J. 26, 1681–1690 (2007). In this cell-free study, direct evidence is provided for the first time that tapasin alone has chaperone and catalytic functions that enable it to influence the peptide repertoire.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Ortmann, B. et al. A critical role for tapasin in the assembly and function of multimeric MHC class I-TAP complexes. Science 277, 1306–1309 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Howarth, M., Williams, A., Tolstrup, A. B. & Elliott, T. Tapasin enhances MHC class I peptide presentation according to peptide half-life. Proc. Natl Acad. Sci. USA 101, 11737–11742 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Dick, T. P. & Cresswell, P. Thiol oxidation and reduction in major histocompatibility complex class I-restricted antigen processing and presentation. Methods Enzymol. 348, 49–54 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Sadasivan, B., Lehner, P. J., Ortmann, B., Spies, T. & Cresswell, P. Roles for calreticulin and a novel glycoprotein, tapasin, in the interaction of MHC class I molecules with TAP. Immunity 5, 103–114 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Lee, S. et al. Structural and functional dissection of human cytomegalovirus US3 in binding major histocompatibility complex class I molecules. J. Virol. 74, 11262–11269 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Park, B. et al. Human cytomegalovirus inhibits tapasin-dependent peptide loading and optimization of the MHC class I peptide cargo for immune evasion. Immunity 20, 71–85 (2004). This study identifies for the first time the interaction between US3 and tapasin and its function in retaining MHC class I molecules in the ER.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Peh, C. A. et al. HLA-B27-restricted antigen presentation in the absence of tapasin reveals polymorphism in mechanisms of HLA class I peptide loading. Immunity 8, 531–542 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Turnquist, H. R. et al. The Ig-like domain of tapasin influences intermolecular interactions. J. Immunol. 172, 2976–2984 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56

    Bennett, E. M., Bennink, J. R., Yewdell, J. W. & Brodsky, F. M. Cutting edge: adenovirus E19 has two mechanisms for affecting class I MHC expression. J. Immunol. 162, 5049–5052 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Tan, P. et al. Recruitment of MHC class I molecules by tapasin into the transporter associated with antigen processing-associated complex is essential for optimal peptide loading. J. Immunol. 168, 1950–1960 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Raghuraman, G., Lapinski, P. E. & Raghavan, M. Tapasin interacts with the membrane-spanning domains of both TAP subunits and enhances the structural stability of TAP1 x TAP2 complexes. J. Biol. Chem. 277, 41786–41794 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    Papadopoulos, M. & Momburg, F. Multiple residues in the transmembrane helix and connecting peptide of mouse tapasin stabilize the transporter associated with the antigen-processing TAP2 subunit. J. Biol. Chem. 282, 9401–9410 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Petersen, J. L. et al. A charged amino acid residue in the transmembrane/cytoplasmic region of tapasin influences MHC class I assembly and maturation. J. Immunol. 174, 962–969 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Andersson, M., Paabo, S., Nilsson, T. & Peterson, P. A. Impaired intracellular transport of class I MHC antigens as a possible means for adenoviruses to evade immune surveillance. Cell 43, 215–222 (1985).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Andersson, M., McMichael, A. & Peterson, P. A. Reduced allorecognition of adenovirus-2 infected cells. J. Immunol. 138, 3960–3966 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Cox, J. H., Bennink, J. R. & Yewdell, J. W. Retention of adenovirus E19 glycoprotein in the endoplasmic reticulum is essential to its ability to block antigen presentation. J. Exp. Med. 174, 1629–1637 (1991).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Burgert, H. G. & Kvist, S. An adenovirus type 2 glycoprotein blocks cell surface expression of human histocompatibility class I antigens. Cell 41, 987–997 (1985). This study, together with reference 61, provides the first example of a viral immune evasion mechanism that targets the MHC class I antigen presentation pathway.

    CAS  Article  Google Scholar 

  65. 65

    Burgert, H. G. & Kvist, S. The E3/19K protein of adenovirus type 2 binds to the domains of histocompatibility antigens required for CTL recognition. EMBO J. 6, 2019–2026 (1987).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Beier, D. C., Cox, J. H., Vining, D. R., Cresswell, P. & Engelhard, V. H. Association of human class I MHC alleles with the adenovirus E3/19K protein. J. Immunol. 152, 3862–3872 (1994).

    CAS  Google Scholar 

  67. 67

    Feuerbach, D. et al. Identification of amino acids within the MHC molecule important for the interaction with the adenovirus protein E3/19K. J. Immunol. 153, 1626–1636 (1994).

    CAS  Google Scholar 

  68. 68

    Flomenberg, P., Gutierrez, E. & Hogan, K. T. Identification of class I MHC regions which bind to the adenovirus E3–19k protein. Mol. Immunol. 31, 1277–1284 (1994).

    CAS  Article  Google Scholar 

  69. 69

    Paabo, S., Bhat, B. M., Wold, W. S. & Peterson, P. A. A short sequence in the COOH-terminus makes an adenovirus membrane glycoprotein a resident of the endoplasmic reticulum. Cell 50, 311–317 (1987).

    CAS  Article  Google Scholar 

  70. 70

    Gabathuler, R., Levy, F. & Kvist, S. Requirements for the association of adenovirus type 2 E3/19K wild-type and mutant proteins with HLA antigens. J. Virol. 64, 3679–3685 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Liu, H., Stafford, W. F. & Bouvier, M. The endoplasmic reticulum lumenal domain of the adenovirus type 2 E3–19K protein binds to peptide-filled and peptide-deficient HLA-A*1101 molecules. J. Virol. 79, 13317–13325 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Severinsson, L., Martens, I. & Peterson, P. A. Differential association between two human MHC class I antigens and an adenoviral glycoprotein. J. Immunol. 137, 1003–1009 (1986).

    CAS  Google Scholar 

  73. 73

    Korner, H. & Burgert, H. G. Down-regulation of HLA antigens by the adenovirus type 2 E3/19K protein in a T-lymphoma cell line. J. Virol. 68, 1442–1448 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Deryckere, F. & Burgert, H. G. Early region 3 of adenovirus type 19 (subgroup D) encodes an HLA-binding protein distinct from that of subgroups B and C. J. Virol. 70, 2832–2841 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Liu, H., Fu, J. & Bouvier, M. Allele- and locus-specific recognition of class I MHC molecules by the immunomodulatory E3–19K protein from adenovirus. J. Immunol. 178, 4567–4575 (2007).

    CAS  Article  Google Scholar 

  76. 76

    Lewis, J. W., Neisig, A., Neefjes, J. & Elliott, T. Point mutations in the α2 domain of HLA-A2.1 define a functionally relevant interaction with TAP. Curr. Biol. 6, 873–883 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Yu, Y. Y. et al. An extensive region of an MHC class I α2 domain loop influences interaction with the assembly complex. J. Immunol. 163, 4427–4433 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Gewurz, B. E. et al. Antigen presentation subverted: structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2. Proc. Natl Acad. Sci. USA 98, 6794–6799 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Byun, M., Wang, X., Pak, M., Hansen, T. H. & Yokoyama, W. M. Cowpox virus exploits the endoplasmic reticulum retention pathway to inhibit MHC class I transport to the cell surface. Cell Host Microbe 2, 306–315 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Dasgupta, A., Hammarlund, E., Slifka, M. K. & Fruh, K. Cowpox virus evades CTL recognition and inhibits the intracellular transport of MHC class I molecules. J. Immunol. 178, 1654–1661 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Yu, Y. Y. et al. Definition and transfer of a serological epitope specific for peptide-empty forms of MHC class I. Int. Immunol. 11, 1897–1906 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Hansen, T. H., Lybarger, L., Yu, L., Mitaksov, V. & Fremont, D. H. Recognition of open conformers of classical MHC by chaperones and monoclonal antibodies. Immunol. Rev. 207, 100–111 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    Elliott, T. & Williams, A. The optimization of peptide cargo bound to MHC class I molecules by the peptide-loading complex. Immunol. Rev. 207, 89–99 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Park, B. & Ahn, K. An essential function of tapasin in quality control of HLA-G molecules. J. Biol. Chem. 278, 14337–14345 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Paquet, M. E., Cohen-Doyle, M., Shore, G. C. & Williams, D. B. Bap29/31 influences the intracellular traffic of MHC class I molecules. J. Immunol. 172, 7548–7555 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Ladasky, J. J. et al. Bap31 enhances the endoplasmic reticulum export and quality control of human class I MHC molecules. J. Immunol. 177, 6172–6181 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Beck, J. C., Hansen, T. H., Cullen, S. E. & Lee, D. R. Slower processing, weaker β2-M association, and lower surface expression of H-2Ld are influenced by its amino terminus. J. Immunol. 137, 916–923 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Williams, D. B., Swiedler, S. J. & Hart, G. W. Intracellular transport of membrane glycoproteins: two closely related histocompatibility antigens differ in their rates of transit to the cell surface. J. Cell Biol. 101, 725–734 (1985).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Neefjes, J. J. & Ploegh, H. L. Allele and locus-specific differences in cell surface expression and the association of HLA class I heavy chain with beta 2-microglobulin: differential effects of inhibition of glycosylation on class I subunit association. Eur. J. Immunol. 18, 801–810 (1988).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Chiu, N. M., Chun, T., Fay, M., Mandal, M. & Wang, C. R. The majority of H2-M3 is retained intracellularly in a peptide-receptive state and traffics to the cell surface in the presence of N-formylated peptides. J. Exp. Med. 190, 423–434 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91

    Myers, N. B., Wormstall, E. & Hansen, T. H. Differences among various class I molecules in competition for beta2m in vivo. Immunogenetics 43, 384–387 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92

    Vembar, S. S. & Brodsky, J. L. One step at a time: endoplasmic reticulum-associated degradation. Nature Rev. Mol. Cell Biol. 9, 944–957 (2008).

    CAS  Article  Google Scholar 

  93. 93

    Hughes, E. A., Hammond, C. & Cresswell, P. Misfolded major histocompatibility complex class I heavy chains are translocated into the cytoplasm and degraded by the proteasome. Proc. Natl Acad. Sci. USA 94, 1896–1901 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Lybarger, L., Wang, X., Harris, M. & Hansen, T. H. Viral immune evasion molecules attack the ER peptide-loading complex and exploit ER-associated degradation pathways. Curr. Opin. Immunol. 17, 71–78 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Wiertz, E. J. et al. The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84, 769–779 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Wiertz, E. J. et al. Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384, 432–438 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Loureiro, J. et al. Signal peptide peptidase is required for dislocation from the endoplasmic reticulum. Nature 441, 894–897 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98

    Powers, C. J. & Fruh, K. Signal peptide-dependent inhibition of MHC class I heavy chain translation by rhesus cytomegalovirus. PLoS Pathog. 4, e1000150 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Lilley, B. N. & Ploegh, H. L. A membrane protein required for dislocation of misfolded proteins from the ER. Nature 429, 834–840 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100

    Ye, Y., Shibata, Y., Yun, C., Ron, D. & Rapoport, T. A. A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429, 841–847 (2004). Together with reference 99, this study identifies the evolutionarily conserved protein derlin 1 as a mammalian cellular component that is required for US11-mediated dislocation of MHC class I molecules from the ER lumen to the cytoplasm.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Mueller, B., Klemm, E. J., Spooner, E., Claessen, J. H. & Ploegh, H. L. SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins. Proc. Natl Acad. Sci. USA 105, 12325–12330 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Mueller, B., Lilley, B. N. & Ploegh, H. L. SEL1L, the homologue of yeast Hrd3p, is involved in protein dislocation from the mammalian ER. J. Cell Biol. 175, 261–270 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    Oda, Y. et al. Derlin-2 and derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. J. Cell Biol. 172, 383–393 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104

    Carvalho, P., Goder, V. & Rapoport, T. A. Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126, 361–373 (2006).

    CAS  Article  PubMed  Google Scholar 

  105. 105

    Boname, J. M. & Stevenson, P. G. MHC class I ubiquitination by a viral PHD/LAP finger protein. Immunity 15, 627–636 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Stevenson, P. G. et al. K3-mediated evasion of CD8+ T cells aids amplification of a latent gamma-herpesvirus. Nature Immunol. 3, 733–740 (2002).

    CAS  Article  Google Scholar 

  107. 107

    Lybarger, L., Wang, X., Harris, M. R., Virgin, H. W. & Hansen, T. H. Virus subversion of the MHC class I peptide-loading complex. Immunity 18, 121–130 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Wang, X. et al. Ubiquitination of serine, threonine, or lysine residues on the cytoplasmic tail can induce ERAD of MHC-I by viral E3 ligase mK3. J. Cell Biol. 177, 613–624 (2007). This report shows that MHV68 protein mK3 ubiquitylates the tail of MHC class I in a sequence-independent manner, supporting the idea that MHC class I molecules are removed from the ER through their cytoplasmic tail and that TAP confers substrate specificity.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    Wang, X., Ye, Y., Lencer, W. & Hansen, T. H. The viral E3 ubiquitin ligase mk3 uses the derlin/p97 endoplasmic reticulum-associated degradation pathway to mediate down-regulation of major histocompatibility complex class I proteins. J. Biol. Chem. 281, 8636–8644 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Hassink, G. C., Barel, M. T., Van Voorden, S. B., Kikkert, M. & Wiertz, E. J. Ubiquitination of MHC class I heavy chains is essential for dislocation by human cytomegalovirus-encoded US2 but not US11. J. Biol. Chem. 281, 30063–30071 (2006).

    CAS  Article  Google Scholar 

  111. 111

    Cadwell, K. & Coscoy, L. Ubiquitination on nonlysine residues by a viral E3 ubiquitin ligase. Science 309, 127–130 (2005).

    CAS  Article  Google Scholar 

  112. 112

    Ciechanover, A. & Ben-Saadon, R. N-terminal ubiquitination: more protein substrates join in. Trends Cell Biol. 14, 103–106 (2004).

    CAS  Article  Google Scholar 

  113. 113

    Binette, J. et al. Requirements for the selective degradation of CD4 receptor molecules by the human immunodeficiency virus type 1 Vpu protein in the endoplasmic reticulum. Retrovirology 4, 75 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Tait, S. W. et al. Apoptosis induction by Bid requires unconventional ubiquitination and degradation of its N-terminal fragment. J. Cell Biol. 179, 1453–1466 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Grou, C. P. et al. Members of the E2D (UbcH5) family mediate the ubiquitination of the conserved cysteine of Pex5p, the peroxisomal import receptor. J. Biol. Chem. 283, 14190–14197 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Kalies, K. U., Allan, S., Sergeyenko, T., Kroger, H. & Romisch, K. The protein translocation channel binds proteasomes to the endoplasmic reticulum membrane. EMBO J. 24, 2284–2293 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Tirosh, B., Furman, M. H., Tortorella, D. & Ploegh, H. L. Protein unfolding is not a prerequisite for endoplasmic reticulum-to-cytosol dislocation. J. Biol. Chem. 278, 6664–6672 (2003).

    CAS  Article  Google Scholar 

  118. 118

    Yoshida, H. ER stress and diseases. FEBS J. 274, 630–658 (2007).

    CAS  Article  Google Scholar 

  119. 119

    Shin, J. S. et al. Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination. Nature 444, 115–118 (2006).

    CAS  Article  Google Scholar 

  120. 120

    De, G. A. et al. MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation. Proc. Natl Acad. Sci. USA 105, 3491–3496 (2008).

    Article  Google Scholar 

  121. 121

    Matsuki, Y. et al. Novel regulation of MHC class II function in B cells. EMBO J. 26, 846–854 (2007). This study describes a functional parallel between immune evasion proteins (kK3, kK5 and mK3) and their cellular homologues (MARCH proteins) by showing that MARCH1 is a key regulator of MHC class II expression in B cells (a finding extended to DCs in reference120).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Stevenson, P. G., Efstathiou, S., Doherty, P. C. & Lehner, P. J. Inhibition of MHC class I-restricted antigen presentation by gamma 2-herpesviruses. Proc. Natl Acad. Sci. USA 97, 8455–8460 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. 123

    Coscoy, L. & Ganem, D. Kaposi's sarcoma-associated herpesvirus encodes two proteins that block cell surface display of MHC class I chains by enhancing their endocytosis. Proc. Natl Acad. Sci. USA 97, 8051–8056 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. 124

    Ishido, S., Wang, C., Lee, B. S., Cohen, G. B. & Jung, J. U. Downregulation of major histocompatibility complex class I molecules by Kaposi's sarcoma-associated herpesvirus K3 and K5 proteins. J. Virol. 74, 5300–5309 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Nathan, J. A. & Lehner, P. J. The trafficking and regulation of membrane receptors by the RING-CH ubiquitin E3 ligases. Exp. Cell Res. 315, 1593–1600 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Thomas, M. et al. Down-regulation of NKG2D and NKp80 ligands by Kaposi's sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity. Proc. Natl Acad. Sci. USA 105, 1656–1661 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127

    Sanchez, D. J., Coscoy, L. & Ganem, D. Functional organization of MIR2, a novel viral regulator of selective endocytosis. J. Biol. Chem. 277, 6124–6130 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. 128

    Coscoy, L., Sanchez, D. J. & Ganem, D. A novel class of herpesvirus-encoded membrane-bound E3 ubiquitin ligases regulates endocytosis of proteins involved in immune recognition. J. Cell Biol. 155, 1265–1273 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    Hewitt, E. W. et al. Ubiquitylation of MHC class I by the K3 viral protein signals internalization and TSG101-dependent degradation. EMBO J. 21, 2418–2429 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. 130

    Duncan, L. M. et al. Lysine-63-linked ubiquitination is required for endolysosomal degradation of class I molecules. EMBO J. 25, 1635–1645 (2006). This study defines the molecular pathway by which the KSHV protein kK3 ubiquitylates MHC class I molecules and thereby induces their endocytosis and lysosomal degradation.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    Mansouri, M. et al. Kaposi sarcoma herpesvirus K5 removes CD31/PECAM from endothelial cells. Blood 108, 1932–1940 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Schwartz, O., Marechal, V., Le, G. S., Lemonnier, F. & Heard, J. M. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nature Med. 2, 338–342 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 133

    Collins, K. L., Chen, B. K., Kalams, S. A., Walker, B. D. & Baltimore, D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391, 397–401 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  134. 134

    Garcia, J. V. & Miller, A. D. Serine phosphorylation-independent downregulation of cell-surface CD4 by Nef. Nature 350, 508–511 (1991).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135

    Sol-Foulon, N. et al. HIV-1 Nef-induced upregulation of DC-SIGN in dendritic cells promotes lymphocyte clustering and viral spread. Immunity 16, 145–155 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  136. 136

    Stumptner-Cuvelette, P. et al. HIV-1 Nef impairs MHC class II antigen presentation and surface expression. Proc. Natl Acad. Sci. USA 98, 12144–12149 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Swigut, T., Shohdy, N. & Skowronski, J. Mechanism for down-regulation of CD28 by Nef. EMBO J. 20, 1593–1604 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  138. 138

    Lama, J., Mangasarian, A. & Trono, D. Cell-surface expression of CD4 reduces HIV-1 infectivity by blocking Env incorporation in a Nef- and Vpu-inhibitable manner. Curr. Biol. 9, 622–631 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  139. 139

    Ross, T. M., Oran, A. E. & Cullen, B. R. Inhibition of HIV-1 progeny virion release by cell-surface CD4 is relieved by expression of the viral Nef protein. Curr. Biol. 9, 613–621 (1999).

    CAS  Article  Google Scholar 

  140. 140

    Roeth, J. F., Williams, M., Kasper, M. R., Filzen, T. M. & Collins, K. L. HIV-1 Nef disrupts MHC-I trafficking by recruiting AP-1 to the MHC-I cytoplasmic tail. J. Cell Biol. 167, 903–913 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Reusch, U. et al. A cytomegalovirus glycoprotein re-routes MHC class I complexes to lysosomes for degradation. EMBO J. 18, 1081–1091 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. 142

    Schaefer, M. R., Wonderlich, E. R., Roeth, J. F., Leonard, J. A. & Collins, K. L. HIV-1 Nef targets MHC-I and CD4 for degradation via a final common β-COP-dependent pathway in T cells. PLoS Pathog. 4, e1000131 (2008). This study defines a model by which the HIV protein Nef differentially sorts MHC class I and CD4 molecules that ultimately are degraded in the lysosome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful for the scientific critiquing of Dr X. Wang. Funding from National Institutes of Health (NIH) grants AI019687 (T.H.H.) and AI045070 (M.B.) is acknowledged.

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Glossary

Proteasome

A giant multicatalytic protease that resides in the cytoplasm and the nucleus. The 20S core, which contains three distinct catalytic subunits, can be appended at either end by a 19S cap or an 11S cap. The binding of two 19S caps to the 20S core forms the 26S proteasome, which degrades polyubiquitylated proteins. In addition to having a crucial role in protein turnover, the proteasome is involved in the first catalytic step in the processing of most, if not all, antigens for MHC class I presentation.

HLA-DM

A non-classical MHC class II molecule that has a crucial role in mediating the catalytic exchange of peptides bound to MHC class II molecules in endosomal and lysosomal compartments of cells.

HLAG

A non-classical MHC class Ib molecule that is involved in the establishment of immune tolerance at the maternal–fetal interface, the major soluble isoforms of which are HLA-G1 and HLA-G5.

Cargo receptor

A protein that is implicated in the trafficking of endoplasmic reticulum (ER)-synthesized proteins between the ER and Golgi.

Signal peptide peptidase

An enzyme that removes signal peptides. Co-translational translocation of most secreted and membrane-bound proteins is initiated by a hydrophobic signal peptide that is recognized by the translocation apparatus. This is then cleaved from the mature protein by signal peptide peptidases after translocation.

E3 ubiquitin ligase

An enzyme that is required to attach the molecular tag ubiquitin to proteins. Depending on the position and number of ubiquitin molecules that are attached, the ubiquitin tag can target proteins for degradation in the proteasomal complex, sort them to specific subcellular compartments or modify their biological activity.

Translocon

A complex of proteins associated with the translocation of nascent proteins across the endoplasmic reticulum (ER) membrane from the cytoplasm to the ER lumen.

MICA and MICB

Ligands for the human natural killer cell activating receptor NKG2D (natural killer group 2, member D). They are closely related stress-inducible molecules that are encoded by genes located in the human MHC region. These molecules are expressed by tumours of epithelial origin and by certain melanomas.

Multivesicular body

An endocytic intermediate organelle in the lysosomal degradative pathway, which contains small vesicles and is surrounded by a limiting membrane.

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Hansen, T., Bouvier, M. MHC class I antigen presentation: learning from viral evasion strategies. Nat Rev Immunol 9, 503–513 (2009). https://doi.org/10.1038/nri2575

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