1 Nature reviews. Immunology 2009 Vol: 9(7):503-513. DOI: 10.1038/nri2575

MHC class I antigen presentation: learning from viral evasion strategies.

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.

Mentions
Figures
Figure 1: The MHC class I antigen presentation pathway is targeted by viral immune evasion proteins.The degradation of proteins by the proteasome generates peptides that are translocated into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). Nascent MHC class I molecules associate with calreticulin, tapasin and ERp57 to form the peptide-loading complex, which facilitates the loading of peptides into the MHC class I peptide-binding groove. Kinetically stable MHC class I molecules then transit to the cell surface. Key stages of the pathway are targeted by immunomodulatory proteins. Proteasomal processing inhibitors, such as Epstein–Barr virus (EBV) nuclear antigen 1 (EBNA1), escape processing by the proteasome. TAP function inhibitors, such as herpes simplex virus (HSV) protein ICP47 and human cytomegalovirus (HCMV) protein US6, block peptide and ATP binding, respectively. Herpesvirus protein UL49.5 and EBV protein BNLF2a also inhibit TAP-mediated peptide transport. Tapasin function inhibitors, such as HCMV protein US3 and adenovirus protein E3-19K, inhibit the peptide optimization and recruiting functions of tapasin, respectively. ER retainers or retrievers of MHC class I molecules, such as adenovirus protein E3-19K and coxpox virus protein 203 (CPXV203) retain MHC class I molecules in the ER. ER-associated degradation inducers, such as HCMV proteins US2 and US11 and mouse herpesvirus 68 (MHV68) protein mK3, target MHC class I molecules for proteasomal degradation. Sorters, such as murine CMV proteins gp48 and HIV-1 protein Nef, divert the trafficking of MHC class I molecules from the Golgi to a lysosomal compartment. Finally, the Kaposi's sarcoma-associated virus (KSHV) proteins kK3 and kK5 induce rapid endocytosis of cell surface MHC class I molecules, leading to lysosomal degradation. Figure 2: Modulation of proteasome and TAP functions by viral immune evasion proteins.The proteasome is the central unit for the degradation of ubiquitylated proteins into peptides, which are then translocated into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). A remarkable property of Epstein–Barr virus nuclear antigen 1 (EBNA1) is to evade proteasomal processing, such that no EBNA1-derived peptides are generated. The ability of EBNA1 to escape proteasomal processing is due to long repeats of glycine and alanine residues in the protein. How these repeats confer inhibitory properties to EBNA1 is unclear, but they do not prevent ubiquitylation of the protein. ICP47 from herpes simplex virus inhibits peptide binding to the cytoplasmic face of the TAP complex. By contrast, US6 from human cytomegalovirus binds to the ER-luminal side of TAP but, remarkably, prevents ATP binding to TAP on the cytoplasmic side. The molecular mechanisms by which ICP47 and US6 block peptide transport are not completely defined, but they seem to exploit the conformational flexibility of TAP that is normally required to transport peptides. Ub, ubiquitin. Figure 3: Modulation of tapasin function and retention of MHC class I molecules by viral immune evasion proteins.Tapasin is a crucial component of the peptide-loading complex (PLC) and has a key role in influencing the generation of the repertoire of peptides presented by MHC class I molecules on the cell surface. The US3 protein from human cytomegalovirus binds to tapasin and inhibits its ability to facilitate the binding of kinetically stable peptides to MHC class I molecules (known as peptide optimization), and E3-19K from adenovirus binds to transporter associated with antigen processing (TAP) and inhibits the ability of tapasin to recruit TAP to the PLC. The molecular basis of these inhibitory effects remains to be more precisely defined. E3-19K also functions by directly targeting MHC class I molecules for retention in the endoplasmic reticulum (ER). The newly identified cowpox virus protein 203 (CPXV203) uses a retention strategy that is similar to that of E3-19K to suppress the presentation of viral peptides. In this figure, the PLC components ERp57 and calreticulin are omitted. 2m, 2-microglobulin. Figure 4: Proposed mechanisms for the modulation of MHC class I presentation pathway by herpesvirus proteins.A | Mouse herpesvirus 68 protein mK3 ubiquitylates MHC class I molecules, which results in their degradation by the proteasome through the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. mK3 binds to its primary binding partner, transporter associated with antigen processing (TAP), which is associated with the MHC class I specific chaperone tapasin (a). After assembling with 2-microglobulin (2m), the MHC class I heavy chain binds the TAP–tapasin complex to await a suitable peptide ligand. TAP orients the mK3 catalytic RING domain such that it is in proximity with the tail of MHC class I molecules (b). The association of mK3 with TAP–tapasin induces the recruitment of an E2 ligase, which results in the polyubiquitylation of the MHC class I tail. 2m also dissociates from the heavy chain (c), perhaps leading to the recruitment of the ER chaperone calnexin into the multimeric complex. Polyubiquitylation with lysine 48 linkages of the MHC class I heavy chain initiates partial denaturation of the heavy chain and the recruitment of the ATPase p97. p97 then facilitates the retro-translocation of the heavy chain to the cytoplasm by a putative dislocation channel that may include derlin 1 and mK3. The MHC class I heavy chain undergoes proteasome-mediated degradation in the cytoplasm mediated by the p97, resulting in the generation of ubiquitin (Ub) monomers and peptides (d). B | Kaposi's sarcoma-associated virus protein kK3 induces polyubiquitylation and internalization of MHC class I molecules. kK3 associates with MHC class I molecules in a post-ER compartment. Initially, kK3 induces the recruitment of the E2 ligase ubiquitin-conjugating enzyme H5 (UBCH5), which adds the first ubiquitin moiety to the tail of the MHC class I heavy chain, and then induces the recruitment of UBC13, which elongates the ubiquitin chain with lysine 63 linkages. The modified MHC class I heavy chain is then endocytosed in an epsin 1-dependent manner. Epsin 1 recruits clathrin, promotes vesicle formation and binds polyubiquitin chains on substrates. The targeted MHC class I molecule is ultimately directed to multivesicular bodies and degraded in the lysosomes. This pathway establishes a paradigm for how MARCH (membrane-associated RING-CH) proteins regulate the expression of MHC class II molecules. Image is modified, with permission, from EMBO Journal Ref. 130 © (2006) Macmillan Publishers Ltd. All rights reserved.
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References
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    • . . . Prior to presenting peptides on the cell surface, MHC class I molecules undergo a stringent maturation process in the endoplasmic reticulum (ER) by transiently interacting with specialized proteins, including calreticulin, ERp57 (also known as PDIA3), tapasin and the transporter associated with antigen processing (TAP)1, 2, 3 (Fig. 1) . . .
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    • . . . Prior to presenting peptides on the cell surface, MHC class I molecules undergo a stringent maturation process in the endoplasmic reticulum (ER) by transiently interacting with specialized proteins, including calreticulin, ERp57 (also known as PDIA3), tapasin and the transporter associated with antigen processing (TAP)1, 2, 3 (Fig. 1) . . .
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    • . . . Numerous viral proteins have been found to inhibit components of the MHC class I assembly pathway, which have been reviewed previously, with an emphasis on their diversity4, 5 . . .
    • . . . Owing to their ability to specifically target MHC class I molecules for rapid ERAD as well as to co-opt physiological ERAD pathways, the use of the immune evasion proteins US2 and US11 of HCMV and mK3 of mouse herpesvirus 68 (MHV68) has provided seminal insights into the molecular mechanisms of ERAD pathways5, 94, 95, 96 (Fig. 1). . . .
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    • . . . In EBNA1, it was shown that the glycine and alanine repeats do not prevent the ubiquitylation of EBNA1 (Ref. 9), nor do they inhibit the proteolytic activity of the 20S subunit13 . . .
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    • . . . The TAP complex is composed of TAP1 and TAP2, each consisting of an amino-terminal transmembrane domain and a carboxy-terminal nucleotide-binding cytoplasmic domain15 (Fig. 1) . . .
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    • . . . Two different viral gene products are well known to exploit the function of TAP (Fig. 1) — herpes simplex virus (HSV) ICP47 protein and human cytomegalovirus (HCMV) US6 protein17, 18, 19, 20, 21 . . .
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    • . . . Two different viral gene products are well known to exploit the function of TAP (Fig. 1) — herpes simplex virus (HSV) ICP47 protein and human cytomegalovirus (HCMV) US6 protein17, 18, 19, 20, 21 . . .
    • . . . US6 interacts directly with the side of TAP that is in the ER lumen19, 34 and can inhibit ATP binding and hydrolysis on the cytoplasmic side by inducing long-range conformational rearrangements in TAP across the ER membrane34, 35 . . .
    • . . . It is worth noting that US6 has no effect on peptide binding by TAP19, 35 . . .
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    • . . . Two different viral gene products are well known to exploit the function of TAP (Fig. 1) — herpes simplex virus (HSV) ICP47 protein and human cytomegalovirus (HCMV) US6 protein17, 18, 19, 20, 21 . . .
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    • . . . More recently, the UL49.5 proteins from herpesviruses that infect cattle, horses and pigs, and EBV BNLF2a protein have also been shown to block TAP-mediated peptide transport22, 23, 24, 25 . . .
    • . . . For example, the bovine herpesvirus UL49.5 targets TAP for proteasomal degradation, and the equine herpesvirus UL49.5 blocks the binding of ATP to TAP23, 38, 39 . . .
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    • . . . More recently, the UL49.5 proteins from herpesviruses that infect cattle, horses and pigs, and EBV BNLF2a protein have also been shown to block TAP-mediated peptide transport22, 23, 24, 25 . . .
    • . . . Finally, the recently identified BNLF2a protein from EBV was shown to prevent the binding of peptides and ATP to TAP25. . . .
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    • . . . Interestingly, it was shown that the ICP47-mediated inhibition of TAP affected certain MHC class I haplotypes more than others26 . . .
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    • . . . This reflects the fact that some MHC class I molecules are less dependent on TAP for peptide loading in the ER than others27 . . .
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    • . . . Evidence suggests that ICP47 may act as a competitive inhibitor by binding with high affinity to the site of antigenic peptides on the cytoplasmic face of TAP28, 29 . . .
    • . . . The association of ICP47 with TAP inhibits peptide binding and turns off ATP hydrolysis and peptide translocation30, 31, without inhibiting ATP binding28, 29 . . .
    • . . . Similarly to ICP47, US6 inhibits TAP in a species-dependent manner, which highlights the remarkable specificity of these proteins as viral inhibitors28, 29, 36, 37 . . .
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    • . . . Evidence suggests that ICP47 may act as a competitive inhibitor by binding with high affinity to the site of antigenic peptides on the cytoplasmic face of TAP28, 29 . . .
    • . . . Similarly to ICP47, US6 inhibits TAP in a species-dependent manner, which highlights the remarkable specificity of these proteins as viral inhibitors28, 29, 36, 37 . . .
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    • . . . However, because ICP47 also induces a conformational change in TAP30, it is possible that this effect may be sufficient to destabilize and inactivate TAP . . .
    • . . . The association of ICP47 with TAP inhibits peptide binding and turns off ATP hydrolysis and peptide translocation30, 31, without inhibiting ATP binding28, 29 . . .
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    • . . . The association of ICP47 with TAP inhibits peptide binding and turns off ATP hydrolysis and peptide translocation30, 31, without inhibiting ATP binding28, 29 . . .
  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) , .
    • . . . The domain of ICP47 that mediates the inhibitory effect is an N-terminal fragment of 32 residues32, 33 . . .
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    • . . . The domain of ICP47 that mediates the inhibitory effect is an N-terminal fragment of 32 residues32, 33 . . .
    • . . . Detailed knowledge of the functions of ICP47, US6, UL49.5 and BNFL2a would not only help to define how some viruses hide from the immune system but also contribute to the refinement of structural and functional models of the PLC33, 42, 43, 44. . . .
  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) , .
    • . . . US6 interacts directly with the side of TAP that is in the ER lumen19, 34 and can inhibit ATP binding and hydrolysis on the cytoplasmic side by inducing long-range conformational rearrangements in TAP across the ER membrane34, 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) , .
    • . . . US6 interacts directly with the side of TAP that is in the ER lumen19, 34 and can inhibit ATP binding and hydrolysis on the cytoplasmic side by inducing long-range conformational rearrangements in TAP across the ER membrane34, 35 . . .
    • . . . It is worth noting that US6 has no effect on peptide binding by TAP19, 35 . . .
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    • . . . Similarly to ICP47, US6 inhibits TAP in a species-dependent manner, which highlights the remarkable specificity of these proteins as viral inhibitors28, 29, 36, 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) , .
    • . . . Similarly to ICP47, US6 inhibits TAP in a species-dependent manner, which highlights the remarkable specificity of these proteins as viral inhibitors28, 29, 36, 37 . . .
  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) , .
    • . . . For example, the bovine herpesvirus UL49.5 targets TAP for proteasomal degradation, and the equine herpesvirus UL49.5 blocks the binding of ATP to TAP23, 38, 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) , .
    • . . . For example, the bovine herpesvirus UL49.5 targets TAP for proteasomal degradation, and the equine herpesvirus UL49.5 blocks the binding of ATP to TAP23, 38, 39 . . .
  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) , .
    • . . . Furthermore, because ICP47, US6, UL49.5 and BNLF2a can modulate peptide binding, ATP binding and ATP hydrolysis, they are useful molecular tools to understand how these events act synergistically to activate TAP function40, 41 . . .
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    • . . . Furthermore, because ICP47, US6, UL49.5 and BNLF2a can modulate peptide binding, ATP binding and ATP hydrolysis, they are useful molecular tools to understand how these events act synergistically to activate TAP function40, 41 . . .
    • . . . To date, the molecular properties of the TAP–tapasin complex are not well characterized, although leucine-rich sequences in the first N-terminal transmembrane helices of TAP1 and TAP2 have been implicated as binding sites for a putative leucine zipper motif in the transmembrane domain of tapasin41, 42, 57, 58, 59 . . .
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    • . . . Detailed knowledge of the functions of ICP47, US6, UL49.5 and BNFL2a would not only help to define how some viruses hide from the immune system but also contribute to the refinement of structural and functional models of the PLC33, 42, 43, 44. . . .
    • . . . To date, the molecular properties of the TAP–tapasin complex are not well characterized, although leucine-rich sequences in the first N-terminal transmembrane helices of TAP1 and TAP2 have been implicated as binding sites for a putative leucine zipper motif in the transmembrane domain of tapasin41, 42, 57, 58, 59 . . .
  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) , .
    • . . . Detailed knowledge of the functions of ICP47, US6, UL49.5 and BNFL2a would not only help to define how some viruses hide from the immune system but also contribute to the refinement of structural and functional models of the PLC33, 42, 43, 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 , .
    • . . . Detailed knowledge of the functions of ICP47, US6, UL49.5 and BNFL2a would not only help to define how some viruses hide from the immune system but also contribute to the refinement of structural and functional models of the PLC33, 42, 43, 44. . . .
    • . . . For example, a characterization of the US3 binding surface on tapasin, possibly through a mutational analysis of tapasin or crystallization of the soluble US3–tapasin complex, may help to further delineate which region in tapasin is involved specifically in peptide optimization44 . . .
    • . . . Tapasin mutants that exhibit impaired interaction with MHC class I molecules44, 55 (M.B., unpublished observations) could guide such studies . . .
  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) , .
    • . . . In the PLC, tapasin stabilizes the groove of MHC class I molecules against irreversible denaturation and maintains it in a peptide-receptive state45, 46, 47, 48 (Fig. 1) . . .
  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) , .
    • . . . In the PLC, tapasin stabilizes the groove of MHC class I molecules against irreversible denaturation and maintains it in a peptide-receptive state45, 46, 47, 48 (Fig. 1) . . .
  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 , .
    • . . . In the PLC, tapasin stabilizes the groove of MHC class I molecules against irreversible denaturation and maintains it in a peptide-receptive state45, 46, 47, 48 (Fig. 1) . . .
    • . . . In addition, tapasin alone can increase the rates of peptide association and dissociation onto MHC class I molecules47 . . .
    • . . . As a consequence of its chaperone-like and catalytic functions, tapasin influences the process of peptide loading in such a way that only those peptides that can form long-lived complexes with MHC class I molecules become part of the presented repertoire47, 49 . . .
  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) , .
    • . . . In the PLC, tapasin stabilizes the groove of MHC class I molecules against irreversible denaturation and maintains it in a peptide-receptive state45, 46, 47, 48 (Fig. 1) . . .
  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) , .
    • . . . As a consequence of its chaperone-like and catalytic functions, tapasin influences the process of peptide loading in such a way that only those peptides that can form long-lived complexes with MHC class I molecules become part of the presented repertoire47, 49 . . .
  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) , .
    • . . . In addition, tapasin physically recruits ERp57 (or calreticulin-associated ERp57)50 and TAP51 to the PLC . . .
  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) , .
    • . . . In addition, tapasin physically recruits ERp57 (or calreticulin-associated ERp57)50 and TAP51 to the PLC . . .
    • . . . The type I transmembrane glycoprotein E3-19K from adenovirus also inhibits a crucial function of tapasin, namely its ability to bridge TAP to MHC class I molecules51 . . .
  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) , .
    • . . . HCMV encodes an immunomodulatory protein, US3, that directly binds to and inhibits tapasin52 (Fig. 3) . . .
  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 , .
    • . . . The association of US3 with tapasin inhibits optimization of peptide cargo and causes MHC class I molecules to be retained in the ER, although substantial amounts of MHC class I molecules can still reach the cell surface53 . . .
    • . . . Furthermore, although the US3–tapasin association has no effect on TAP recruitment by tapasin53, it would be of interest to determine whether this association inhibits the recruitment of ERp57, as this may provide a strategy to better understand the functional relationship between this protein and tapasin . . .
  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) , .
    • . . . This differential effect of US3 on MHC class I cell surface expression highlights the finding that MHC class I molecules are not all equally dependent on tapasin for maturation in the ER54 . . .
  55. Turnquist, H. R. et al. The Ig-like domain of tapasin influences intermolecular interactions. J. Immunol. 172, 2976-2984 (2004) , .
    • . . . Tapasin mutants that exhibit impaired interaction with MHC class I molecules44, 55 (M.B., unpublished observations) could guide such studies . . .
  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) , .
    • . . . However, unlike US3, E3-19K mediates this activity by binding to TAP56 (Fig. 3), without blocking peptide transport . . .
    • . . . It was suggested that this strategy may be an alternative mechanism evolved by adenoviruses to downregulate the expression of MHC class I molecules that are only weakly targeted by E3-19K through direct interactions56 (see later) . . .
    • . . . The association of E3-19K with TAP inhibits the formation of the TAP–tapasin complex and, therefore, impairs the inclusion of TAP into the PLC56 . . .
  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) , .
    • . . . To date, the molecular properties of the TAP–tapasin complex are not well characterized, although leucine-rich sequences in the first N-terminal transmembrane helices of TAP1 and TAP2 have been implicated as binding sites for a putative leucine zipper motif in the transmembrane domain of tapasin41, 42, 57, 58, 59 . . .
    • . . . Residues in the transmembrane domain of tapasin that are crucial for the stabilization of TAP1 (Refs 57, 60) and TAP2 (Ref. 59) have also been identified . . .
  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) , .
    • . . . To date, the molecular properties of the TAP–tapasin complex are not well characterized, although leucine-rich sequences in the first N-terminal transmembrane helices of TAP1 and TAP2 have been implicated as binding sites for a putative leucine zipper motif in the transmembrane domain of tapasin41, 42, 57, 58, 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) , .
    • . . . To date, the molecular properties of the TAP–tapasin complex are not well characterized, although leucine-rich sequences in the first N-terminal transmembrane helices of TAP1 and TAP2 have been implicated as binding sites for a putative leucine zipper motif in the transmembrane domain of tapasin41, 42, 57, 58, 59 . . .
    • . . . Residues in the transmembrane domain of tapasin that are crucial for the stabilization of TAP1 (Refs 57, 60) and TAP2 (Ref. 59) have also been identified . . .
  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) , .
    • . . . Residues in the transmembrane domain of tapasin that are crucial for the stabilization of TAP1 (Refs 57, 60) and TAP2 (Ref. 59) have also been identified . . .
  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) , .
    • . . . For example, adenovirus E3-19K directly associates with MHC class I molecules and blocks their transport out of the ER61, 62, 63, 64 (Fig. 3) . . .
  62. Andersson, M., McMichael, A. & Peterson, P. A. Reduced allorecognition of adenovirus-2 infected cells. J. Immunol. 138, 3960-3966 (1987) , .
    • . . . For example, adenovirus E3-19K directly associates with MHC class I molecules and blocks their transport out of the ER61, 62, 63, 64 (Fig. 3) . . .
  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) , .
    • . . . For example, adenovirus E3-19K directly associates with MHC class I molecules and blocks their transport out of the ER61, 62, 63, 64 (Fig. 3) . . .
    • . . . This association is mediated by the ER-luminal domains of both proteins, and the retention effect is mediated by the cytoplasmic domain of E3-19K63, 65, 66, 67, 68, 69, 70, 71 . . .
    • . . . Finally, the finding that MHC class I molecules that are associated with E3-19K can still be loaded with antigenic peptides63, 71 suggests that E3-19K binds to the outer surface of the peptide-binding groove, possibly in a way that is similar to how US2 binds to MHC class I molecules78. . . .
  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 , .
    • . . . For example, adenovirus E3-19K directly associates with MHC class I molecules and blocks their transport out of the ER61, 62, 63, 64 (Fig. 3) . . .
  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) , .
    • . . . This association is mediated by the ER-luminal domains of both proteins, and the retention effect is mediated by the cytoplasmic domain of E3-19K63, 65, 66, 67, 68, 69, 70, 71 . . .
  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) , .
    • . . . This association is mediated by the ER-luminal domains of both proteins, and the retention effect is mediated by the cytoplasmic domain of E3-19K63, 65, 66, 67, 68, 69, 70, 71 . . .
    • . . . Evidence was also provided indicating that E3-19K displays an allele and locus specificity towards MHC class I molecules and has a preference for HLA-A over HLA-B molecules; E3-19K does not detectably associate with HLA-C molecules under identical conditions66, 72, 73, 74, 75 . . .
  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) , .
    • . . . This association is mediated by the ER-luminal domains of both proteins, and the retention effect is mediated by the cytoplasmic domain of E3-19K63, 65, 66, 67, 68, 69, 70, 71 . . .
    • . . . Studies of the interaction of E3-19K with different HLA-A molecules have shown that specific residues in the peptide-binding groove, including residue 56 of MHC class I, have crucial roles in modulating the association and ER retention of MHC class I molecules by E3-19K67, 68, 75 . . .
  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) , .
    • . . . This association is mediated by the ER-luminal domains of both proteins, and the retention effect is mediated by the cytoplasmic domain of E3-19K63, 65, 66, 67, 68, 69, 70, 71 . . .
    • . . . Studies of the interaction of E3-19K with different HLA-A molecules have shown that specific residues in the peptide-binding groove, including residue 56 of MHC class I, have crucial roles in modulating the association and ER retention of MHC class I molecules by E3-19K67, 68, 75 . . .
  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) , .
    • . . . This association is mediated by the ER-luminal domains of both proteins, and the retention effect is mediated by the cytoplasmic domain of E3-19K63, 65, 66, 67, 68, 69, 70, 71 . . .
  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) , .
    • . . . This association is mediated by the ER-luminal domains of both proteins, and the retention effect is mediated by the cytoplasmic domain of E3-19K63, 65, 66, 67, 68, 69, 70, 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) , .
    • . . . This association is mediated by the ER-luminal domains of both proteins, and the retention effect is mediated by the cytoplasmic domain of E3-19K63, 65, 66, 67, 68, 69, 70, 71 . . .
    • . . . Evidence has been provided showing that soluble E3-19K targets both immature and mature MHC class I molecules, but has a stronger association with the mature form71 . . .
    • . . . Interestingly, the association of E3-19K with immature MHC class I molecules stabilizes the peptide-binding groove against conformational denaturation71 . . .
    • . . . Finally, the finding that MHC class I molecules that are associated with E3-19K can still be loaded with antigenic peptides63, 71 suggests that E3-19K binds to the outer surface of the peptide-binding groove, possibly in a way that is similar to how US2 binds to MHC class I molecules78. . . .
  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) , .
    • . . . Evidence was also provided indicating that E3-19K displays an allele and locus specificity towards MHC class I molecules and has a preference for HLA-A over HLA-B molecules; E3-19K does not detectably associate with HLA-C molecules under identical conditions66, 72, 73, 74, 75 . . .
  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) , .
    • . . . Evidence was also provided indicating that E3-19K displays an allele and locus specificity towards MHC class I molecules and has a preference for HLA-A over HLA-B molecules; E3-19K does not detectably associate with HLA-C molecules under identical conditions66, 72, 73, 74, 75 . . .
  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) , .
    • . . . Evidence was also provided indicating that E3-19K displays an allele and locus specificity towards MHC class I molecules and has a preference for HLA-A over HLA-B molecules; E3-19K does not detectably associate with HLA-C molecules under identical conditions66, 72, 73, 74, 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) , .
    • . . . Evidence was also provided indicating that E3-19K displays an allele and locus specificity towards MHC class I molecules and has a preference for HLA-A over HLA-B molecules; E3-19K does not detectably associate with HLA-C molecules under identical conditions66, 72, 73, 74, 75 . . .
    • . . . Studies of the interaction of E3-19K with different HLA-A molecules have shown that specific residues in the peptide-binding groove, including residue 56 of MHC class I, have crucial roles in modulating the association and ER retention of MHC class I molecules by E3-19K67, 68, 75 . . .
    • . . . Finally, studies of E3-19K from different adenovirus subgroups in combination with different MHC class I haplotypes may help to further define paradigms for how MHC class I substrate specificity is established for ER retention75. . . .
  76. Lewis, J. W., Neisig, A., Neefjes, J. & Elliott, T. Point mutations in the 2 domain of HLA-A2.1 define a functionally relevant interaction with TAP. Curr. Biol. 6, 873-883 (1996) , .
    • . . . This finding implies that, when targeting MHC class I molecules, E3-19K is unlikely to compete with components of the MHC class I assembly pathway, which are thought to bind at the C-terminal end of the peptide-binding groove76, 77 . . .
  77. Yu, Y. Y. et al. An extensive region of an MHC class I 2 domain loop influences interaction with the assembly complex. J. Immunol. 163, 4427-4433 (1999) , .
    • . . . This finding implies that, when targeting MHC class I molecules, E3-19K is unlikely to compete with components of the MHC class I assembly pathway, which are thought to bind at the C-terminal end of the peptide-binding groove76, 77 . . .
  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) , .
    • . . . Finally, the finding that MHC class I molecules that are associated with E3-19K can still be loaded with antigenic peptides63, 71 suggests that E3-19K binds to the outer surface of the peptide-binding groove, possibly in a way that is similar to how US2 binds to MHC class I molecules78. . . .
    • . . . Indeed, the nature of the direct binding of US2 to fully assembled HLA-A2 was revealed by the analysis of the crystal structure of the complex78 . . .
  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) , .
    • . . . More recently, it was reported that cowpox virus (CPXV) encodes a protein known as CPXV203, which exploits the ER retention pathway in a similar manner to E3-19K79, 80 (Fig. 3) . . .
    • . . . CPXV203 is a soluble protein that causes MHC class I retention in the ER owing to a C-terminal ER retention motif79 . . .
  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) , .
    • . . . More recently, it was reported that cowpox virus (CPXV) encodes a protein known as CPXV203, which exploits the ER retention pathway in a similar manner to E3-19K79, 80 (Fig. 3) . . .
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    • . . . This loop contains a linear epitope that is specific for the conformation-sensitive monoclonal antibody 64-3-7 (Ref. 81) . . .
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    • . . . An analogous loop on MHC class II molecules was suggested to be the binding site of HLA-DM82, 83 . . .
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    • . . . An analogous loop on MHC class II molecules was suggested to be the binding site of HLA-DM82, 83 . . .
  84. Park, B. & Ahn, K. An essential function of tapasin in quality control of HLA-G molecules. J. Biol. Chem. 278, 14337-14345 (2003) , .
    • . . . Similar retrograde transport studies have been reported for the non-classical MHC molecule HLA-G84 and the B cell receptor-associated protein 31 (BAP31) and BAP29, which are putative cargo receptors that have been implicated in the retrieval of MHC class I molecules from post-ER compartments85, 86 . . .
  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) , .
    • . . . Similar retrograde transport studies have been reported for the non-classical MHC molecule HLA-G84 and the B cell receptor-associated protein 31 (BAP31) and BAP29, which are putative cargo receptors that have been implicated in the retrieval of MHC class I molecules from post-ER compartments85, 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) , .
    • . . . Similar retrograde transport studies have been reported for the non-classical MHC molecule HLA-G84 and the B cell receptor-associated protein 31 (BAP31) and BAP29, which are putative cargo receptors that have been implicated in the retrieval of MHC class I molecules from post-ER compartments85, 86 . . .
  87. Beck, J. C., Hansen, T. H., Cullen, S. E. & Lee, D. R. Slower processing, weaker 2-M association, and lower surface expression of H-2Ld are influenced by its amino terminus. J. Immunol. 137, 916-923 (1986) , .
    • . . . Interestingly, classical MHC class I molecules show dramatic isotypic differences in their relative peptide binding efficiency, and this results in their disparate assembly kinetics and chaperone dependencies87, 88, 89 . . .
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    • . . . Interestingly, classical MHC class I molecules show dramatic isotypic differences in their relative peptide binding efficiency, and this results in their disparate assembly kinetics and chaperone dependencies87, 88, 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) , .
    • . . . Interestingly, classical MHC class I molecules show dramatic isotypic differences in their relative peptide binding efficiency, and this results in their disparate assembly kinetics and chaperone dependencies87, 88, 89 . . .
  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) , .
    • . . . The MHC class Ib molecule H2-M3 provides an extreme example of peptide levels limiting maturation90; a paucity of cellular N-formylated peptide ligands results in the ER retention of H2-M3 heavy chains, which can be induced on the cell surface after bacterial infection . . .
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    • . . . In addition, an extensive pool of MHC class Ia and Ib heavy chains have to compete for what can be a limiting pool of 2-microglobulin (2m) in the ER lumen91 . . .
  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) , .
    • . . . The elimination of incompletely assembled or misfolded nascent glycoproteins, including MHC molecules, occurs by a process collectively termed ER-associated degradation (ERAD)92 . . .
  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) , .
    • . . . Although there are preliminary data showing that unassembled MHC class I heavy chains undergo ERAD, the slow kinetics of this process in the absence of immune evasion proteins make it difficult to dissect its molecule mechanisms93 . . .
  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) , .
    • . . . Owing to their ability to specifically target MHC class I molecules for rapid ERAD as well as to co-opt physiological ERAD pathways, the use of the immune evasion proteins US2 and US11 of HCMV and mK3 of mouse herpesvirus 68 (MHV68) has provided seminal insights into the molecular mechanisms of ERAD pathways5, 94, 95, 96 (Fig. 1). . . .
  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) , .
    • . . . Owing to their ability to specifically target MHC class I molecules for rapid ERAD as well as to co-opt physiological ERAD pathways, the use of the immune evasion proteins US2 and US11 of HCMV and mK3 of mouse herpesvirus 68 (MHV68) has provided seminal insights into the molecular mechanisms of ERAD pathways5, 94, 95, 96 (Fig. 1). . . .
  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) , .
    • . . . Owing to their ability to specifically target MHC class I molecules for rapid ERAD as well as to co-opt physiological ERAD pathways, the use of the immune evasion proteins US2 and US11 of HCMV and mK3 of mouse herpesvirus 68 (MHV68) has provided seminal insights into the molecular mechanisms of ERAD pathways5, 94, 95, 96 (Fig. 1). . . .
    • . . . Pioneering studies showed that US2 associates with the SEC61 translocon, suggesting the model that ERAD substrates leave the ER the same way they enter — that is, by their N terminus96 . . .
  97. Loureiro, J. et al. Signal peptide peptidase is required for dislocation from the endoplasmic reticulum. Nature 441, 894-897 (2006) , .
    • . . . However, in cells US2 probably interacts with nascent MHC class I molecules, as US2 (but not US11) is physically associated with signal peptide peptidase97 . . .
  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) , .
    • . . . Interestingly, in addition to US2 and US11, rhesus monkey CMV expresses the immune evasion protein rh178, which inhibits heavy chain translation in a signal peptide-dependent manner, thereby enabling it to target an extensive family of MHC class I gene products98. . . .
  99. Lilley, B. N. & Ploegh, H. L. A membrane protein required for dislocation of misfolded proteins from the ER. Nature 429, 834-840 (2004) , .
    • . . . For example, derlin 1 (the mammalian homologue of yeast Der1p) was first identified by its physical association with US11–MHC class I heavy chains and was shown to be required for US11-induced dislocation of heavy chains99, 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 , .
    • . . . For example, derlin 1 (the mammalian homologue of yeast Der1p) was first identified by its physical association with US11–MHC class I heavy chains and was shown to be required for US11-induced dislocation of heavy chains99, 100 . . .
  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) , .
    • . . . Derlin 1 then recruits other members of a putative dislocation core complex, including E3 ubiquitin ligases and SEL1L (the mammalian homologue of yeast Hrd3p)101 . . .
    • . . . SEL1L is found in the ER lumen and potentially bridges substrate recognition by lectin-like chaperone proteins and substrate dislocation101 . . .
  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) , .
    • . . . Both derlin 1 and SEL1L have recently been implicated in degradation pathways that do not involve viral immune evasion proteins, which suggests that this pathway is used for general glycoprotein quality control102, 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) , .
    • . . . Both derlin 1 and SEL1L have recently been implicated in degradation pathways that do not involve viral immune evasion proteins, which suggests that this pathway is used for general glycoprotein quality control102, 103 . . .
  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) , .
    • . . . The existence of multiple pathways initiating ERAD is supported by elegant studies in yeast that have defined three distinct membrane core complexes that service misfolded proteins with domains in the ER lumen (ERAD-L), proteins with intramembrane domains (ERAD-M) or proteins with cytoplasmic domains (ERAD-C)104 . . .
  105. Boname, J. M. & Stevenson, P. G. MHC class I ubiquitination by a viral PHD/LAP finger protein. Immunity 15, 627-636 (2001) , .
    • . . . The MHV68 E3 ligase mK3 specifically ubiquitylates mouse MHC class I heavy chains and targets them for ERAD105 (Fig. 1) . . .
  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) , .
    • . . . During infection, the expression of mK3 allows the virus to maintain a higher level of latency and reduces the number of antiviral CTLs106. mK3 can be found associated with nascent MHC class I heavy chains only in the presence of TAP, its main binding partner107 . . .
  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) , .
    • . . . During infection, the expression of mK3 allows the virus to maintain a higher level of latency and reduces the number of antiviral CTLs106. mK3 can be found associated with nascent MHC class I heavy chains only in the presence of TAP, its main binding partner107 . . .
  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 , .
    • . . . It is important to note that the specificity of substrate ubiquitylation is based on the proximity of the catalytic RING–CH (cysteine and histidine) domain of mK3 to the tail of the heavy chain108 . . .
    • . . . More specifically, studies of mK3 and its homologue kK3 from KSHV (discussed later) were the first to define non-conventional forms of substrate ubiquitylation through ester (serine or threonine) or thioester (cysteine) linkages, respectively108, 111 . . .
    • . . . Alternatively, the finding that mK3 ubiquitylates the C-terminal tail of MHC class I heavy chains suggests a simpler model in which ERAD substrates can be removed vectorially (that is, cytoplasmic tail first)108. . . .
  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) , .
    • . . . Similar to US11, mK3 is found in association with derlin 1, and the activity of mK3 in MHC class I dislocation depends on the ATPase p97 (Ref. 109) . . .
  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) , .
    • . . . However, the mechanism by which US11 achieves protein degradation is unclear: it is not known whether US11 recruits a specific E3 ubiquitin ligase, whether MHC class I heavy chains are directly ubiquitylated in the presence of US11 or whether a protein that associates with MHC class I molecules is ubiquitylated instead110 . . .
  111. Cadwell, K. & Coscoy, L. Ubiquitination on nonlysine residues by a viral E3 ubiquitin ligase. Science 309, 127-130 (2005) , .
    • . . . More specifically, studies of mK3 and its homologue kK3 from KSHV (discussed later) were the first to define non-conventional forms of substrate ubiquitylation through ester (serine or threonine) or thioester (cysteine) linkages, respectively108, 111 . . .
  112. Ciechanover, A. & Ben-Saadon, R. N-terminal ubiquitination: more protein substrates join in. Trends Cell Biol. 14, 103-106 (2004) , .
    • . . . Prior to these studies, it was thought that only lysine residues, or perhaps the N termini of substrates, were ubiquitylated112 . . .
  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) , .
    • . . . Now, residues other than lysine are known to act as substrates for ubiquitin conjugation in physiological pathways involving cellular ubiquitin ligases113, 114, 115 . . .
  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) , .
    • . . . Now, residues other than lysine are known to act as substrates for ubiquitin conjugation in physiological pathways involving cellular ubiquitin ligases113, 114, 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) , .
    • . . . Now, residues other than lysine are known to act as substrates for ubiquitin conjugation in physiological pathways involving cellular ubiquitin ligases113, 114, 115 . . .
  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) , .
    • . . . Although studies of yeast support this model116, US2-mediated dislocation accommodates a tightly folded domain of a size that is not predicted to be tolerated by an unmodified translocon117 . . .
  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) , .
    • . . . Although studies of yeast support this model116, US2-mediated dislocation accommodates a tightly folded domain of a size that is not predicted to be tolerated by an unmodified translocon117 . . .
  118. Yoshida, H. ER stress and diseases. FEBS J. 274, 630-658 (2007) , .
    • . . . These findings are likely to continue to extend beyond antigen presentation to numerous other cellular processes, many of which are relevant to disease development118. . . .
  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) , .
  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) , .
    • . . . The homologous ligases in mice and humans were termed MARCH1–MARCH10 (Box 1), and MARCH1 was recently identified as a key regulator of MHC class II cell surface expression in B cells and DCs120, 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) , .
    • . . . The homologous ligases in mice and humans were termed MARCH1–MARCH10 (Box 1), and MARCH1 was recently identified as a key regulator of MHC class II cell surface expression in B cells and DCs120, 121 . . .
  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) , .
    • . . . The KSHV proteins kK3 and kK5 are highly homologous to mK3 of MHV68 (Refs 122–124) (Fig. 1) and are also E3 ubiquitin ligases . . .
  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) , .
  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) , .
  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) , .
    • . . . kK3 seems to specifically detect human MHC class I molecules, whereas kK5 downregulates the expression of a large number of other cell surface receptors, including CD31 (also known as PECAM1), CD166 (also known as ALCAM), interferon- receptor, intercellular adhesion molecule 1 (ICAM1), CD86 (also known as B7.2), CD144 (also known as VE-cadherin and cadherin 5), activation-induced C-type lectin (AICL; also known as CLEC2B) and MHC class I polypeptide-related sequence A (MICA) and MICB125 . . .
  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) , .
    • . . . The ability of kK5 to downregulate AICL, MICA and MICB is of particular importance because these proteins are ligands for the natural killer (NK) cell activating receptors NKG2D (NK group 2, member D) and NKp80, respectively, thereby providing KSHV with an immune evasion strategy for NK cell lysis126 . . .
    • . . . It should also be noted that kK5 downregulation of cell surface MICA expression does not involve ER or lysosomal degradation126. . . .
  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) , .
    • . . . Although the transmembrane domains of kK3 and kK5 have been implicated in substrate recognition, it remains unclear how kK5 can detect so many structurally unrelated substrates127 . . .
  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) , .
    • . . . Although kK3 mainly resides in the ER, it has been shown to ubiquitylate post-ER (endoglycosidase H resistant) MHC class I heavy chains128, 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) , .
    • . . . Although kK3 mainly resides in the ER, it has been shown to ubiquitylate post-ER (endoglycosidase H resistant) MHC class I heavy chains128, 129 . . .
    • . . . This kK3-mediated internalization of cell surface MHC class I molecules is clathrin dependent and involves epsin 1 and TSG101 (tumour susceptibility gene 101)129, 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 , .
  131. Mansouri, M. et al. Kaposi sarcoma herpesvirus K5 removes CD31/PECAM from endothelial cells. Blood 108, 1932-1940 (2006) , .
    • . . . For example, in cell lines expressing kK5, a fraction of newly synthesized CD31 is ubiquitylated in the ER and degraded by the proteasome131 . . .
  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) , .
    • . . . The HIV-1 protein Nef evades CTL detection by downregulating the expression of MHC class I molecules132, 133 (Fig. 1) . . .
  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) , .
    • . . . The HIV-1 protein Nef evades CTL detection by downregulating the expression of MHC class I molecules132, 133 (Fig. 1) . . .
  134. Garcia, J. V. & Miller, A. D. Serine phosphorylation-independent downregulation of cell-surface CD4 by Nef. Nature 350, 508-511 (1991) , .
    • . . . However, Nef has a more pleiotropic effect on HIV-1 infection by also altering the sorting of several immune molecules, including MHC class I and II molecules, CD4, CD28 and DC-specific ICAM3-grabbing non-integrin (DC-SIGN)134, 135, 136, 137 . . .
  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) , .
    • . . . However, Nef has a more pleiotropic effect on HIV-1 infection by also altering the sorting of several immune molecules, including MHC class I and II molecules, CD4, CD28 and DC-specific ICAM3-grabbing non-integrin (DC-SIGN)134, 135, 136, 137 . . .
  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) , .
    • . . . However, Nef has a more pleiotropic effect on HIV-1 infection by also altering the sorting of several immune molecules, including MHC class I and II molecules, CD4, CD28 and DC-specific ICAM3-grabbing non-integrin (DC-SIGN)134, 135, 136, 137 . . .
  137. Swigut, T., Shohdy, N. & Skowronski, J. Mechanism for down-regulation of CD28 by Nef. EMBO J. 20, 1593-1604 (2001) , .
    • . . . However, Nef has a more pleiotropic effect on HIV-1 infection by also altering the sorting of several immune molecules, including MHC class I and II molecules, CD4, CD28 and DC-specific ICAM3-grabbing non-integrin (DC-SIGN)134, 135, 136, 137 . . .
  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) , .
    • . . . The Nef-induced downregulation of its receptor, CD4, prevents superinfection and optimizes viral particle production138, 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) , .
    • . . . The Nef-induced downregulation of its receptor, CD4, prevents superinfection and optimizes viral particle production138, 139 . . .
  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) , .
    • . . . Nef induces the internalization of CD4 after it has reached the cell surface, but it uses the clathrin adaptor AP1 (adaptor protein 1) to divert the trafficking of MHC class I molecules directly from the trans Golgi network to an endocytic compartment before they reach the cell surface140; murine cytomegalovirus protein gp48 may similarly alter the trafficking of MHC class I molecules141 . . .
  141. Reusch, U. et al. A cytomegalovirus glycoprotein re-routes MHC class I complexes to lysosomes for degradation. EMBO J. 18, 1081-1091 (1999) , .
    • . . . Nef induces the internalization of CD4 after it has reached the cell surface, but it uses the clathrin adaptor AP1 (adaptor protein 1) to divert the trafficking of MHC class I molecules directly from the trans Golgi network to an endocytic compartment before they reach the cell surface140; murine cytomegalovirus protein gp48 may similarly alter the trafficking of MHC class I molecules141 . . .
  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 -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 , .
    • . . . Despite this disparate Nef-induced sorting, both CD4 and MHC class I molecules end up in the same multivesicular bodies, ultimately leading to their degradation in lysosomes142 . . .
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