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The Ins and Outs of Intracellular Peptides and Antigen Presentation by MHC Class I Molecules

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Dislocation and Degradation of Proteins from the Endoplasmic Reticulum

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 300))

Abstract

MHC class I molecules present small intracellular generated fragments to the outside surveying immune system. This is the result of a series of biochemical processes involving biosynthesis, degradation, translocation, intracellular transport, diffusion, and many more. Critical intermediates and end products of this cascade of events are peptides. The peptides are generated by the proteasome, degraded by peptidases unless transported into the ER where another peptidase and MHC class I molecules are waiting. Unless peptides bind to MHC class I molecules, they are released from the ER and enter the cytoplasm by a system resembling the ERAD pathway in many aspects. The cycle of peptides over the ER membrane with the proteasome at the input site and peptidases or MHC class I molecules on the output site are central in the MHC class I antigen presentation pathway and this review.

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References

  • Abele R, Tampe R (2004) The ABCs of immunology: structure and function of TAP, the transporter associated with antigen processing. Physiology (Bethesda) 19:216–224

    CAS  Google Scholar 

  • Arnold D, Faath S, Rammensee H, Schild H (1995) Cross-priming of minor histocompatibility antigen-specific cytotoxic T cells upon immunization with the heat shock protein gp96. J Exp Med 182:885–889

    Article  CAS  PubMed  Google Scholar 

  • Balow RM, Tomkinson B, Ragnarsson U, Zetterqvist O (1986) Purification, substrate specificity, classification of tripeptidyl peptidase II. J Biol Chem 261:2409–2417

    CAS  PubMed  Google Scholar 

  • Barelli H, Ahmad S, Kostka P, Fox JA, Daniel EE, Vincent JP, Checler F (1989) Neuropeptide-hydrolysing activities in synaptosomal fractions from dog ileum myenteric, deep muscular and submucous plexi. Their participation in neurotensin inactivation. Peptides 10:1055–1061

    Article  CAS  PubMed  Google Scholar 

  • Basta S, Chen W, Bennink JR, Yewdell JW (2002) Inhibitory effects of cytomegalovirus proteins US2 and US11 point to contributions from direct priming and cross-priming in induction of vaccinia virus-specific CD8(+) T cells. J Immunol 168:5403–5408

    CAS  PubMed  Google Scholar 

  • Beck S, Kelly A, Radley E, Khurshid F, Alderton RP, Trowsdale J (1992) DNA sequence analysis of 66 kb of the human MHC class II region encoding a cluster of genes for antigen processing. J Mol Biol 228:433–441

    Article  CAS  PubMed  Google Scholar 

  • Ben-Arieh SV, Zimerman B, Smorodinsky NI, Yaacubovicz M, Schechter C, Bacik I, Gibbs J, Bennink JR, Yewdell JW, Coligan JE et al (2001) Human cytomegalovirus protein US2 interferes with the expression of human HFE, a nonclassical class I major histocompatibility complex molecule that regulates iron homeostasis. J Virol 75:10557–10562

    Article  CAS  PubMed  Google Scholar 

  • Bouvier M, Wiley DC (1994) Importance of peptide amino and carboxyl termini to the stability of MHC class I molecules. Science 265:398–402

    CAS  PubMed  Google Scholar 

  • Breslin HJ, Miskowski TA, Kukla MJ, Leister WH, De Winter HL, Gauthier DA, Somers MV, Peeters DC, Roevens PW (2002) Design, synthesis, tripeptidyl peptidase II inhibitory activity of a novel series of (S)-2,3-dihydro-2-(4-alkyl-1H-imidazol-2-yl)-1H-indoles. J Med Chem 45:5303–5310

    Article  CAS  PubMed  Google Scholar 

  • Brocke P, Armandola E, Garbi N, Hammerling GJ (2003) Downmodulation of antigen presentation by H2-O in B cell lines and primary B lymphocytes. Eur J Immunol 33:411–421

    Article  CAS  PubMed  Google Scholar 

  • Cascio P, Hilton C, Kisselev AF, Rock KL, Goldberg AL (2001) 26S proteasomes and immunoproteasomes produce mainly N-extended versions of an antigenic peptide. EMBO J 20:2357–2366

    Article  CAS  PubMed  Google Scholar 

  • Castelli C, Rivoltini L, Rini F, Belli F, Testori A, Maio M, Mazzaferro V, Coppa J, Srivastava PK, Parmiani G (2004) Heat shock proteins: biological functions and clinical application as personalized vaccines for human cancer. Cancer Immunol Immunother 53:227–233

    Article  CAS  PubMed  Google Scholar 

  • Chen M, Abele R, Tampe R (2004) Functional non-equivalence of ABC signature motifs in the transporter associated with antigen processing (TAP). J Biol Chem 279:46073–46081

    CAS  PubMed  Google Scholar 

  • Chen W, Bennink JR, Yewdell JW (2001) Quantitating presentation of MHC class I-restricted antigens. Methods Mol Biol 156:245–254

    CAS  PubMed  Google Scholar 

  • Chien HC, Lin LL, Chao SH, Chen CC, Wang WC, Shaw CY, Tsai YC, Hu HY, Hsu WH (2002) Purification, characterization, genetic analysis of a leucine aminopeptidase from Aspergillus sojae. Biochim Biophys Acta 1576:119–126

    CAS  PubMed  Google Scholar 

  • Cresswell P, Bangia N, Dick T, Diedrich G (1999) The nature of the MHC class I peptide loading complex. Immunol Rev 172:21–28

    CAS  PubMed  Google Scholar 

  • Dauch P, Barelli H, Vincent JP, Checler F (1991) Fluorimetric assay of the neurotensindegrading metalloendopeptidase, endopeptidase 24.16. Biochem J 280:421–426

    CAS  PubMed  Google Scholar 

  • Elliott T, Smith M, Driscoll P, McMichael A (1993) Peptide selection by class Imolecules of the major histocompatibility complex. Curr Biol 3:854–866

    Article  CAS  PubMed  Google Scholar 

  • Fruci D, Niedermann G, Butler RH, van Endert PM (2001) Efficient MHC class I-independent amino-terminal trimming of epitope precursor peptides in the endoplasmic reticulum. Immunity 15:467–476

    Article  CAS  PubMed  Google Scholar 

  • Galocha B, Hill A, Barnett BC, Dolan A, Raimondi A, Cook RF, Brunner J, McGeoch DJ, Ploegh HL (1997) 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

    Article  CAS  PubMed  Google Scholar 

  • Garbi N, Tan P, Diehl AD, Chambers BJ, Ljunggren HG, Momburg F, Hammerling GJ (2000) Impaired immune responses and altered peptide repertoire in tapasindeficient mice. Nat Immunol 1:234–238

    Article  CAS  PubMed  Google Scholar 

  • Geier E, Pfeifer G, Wilm M, Lucchiari-Hartz M, Baumeister W, Eichmann K, Niedermann G (1999) A giant protease with potential to substitute for some functions of the proteasome. Science 283:978–981

    Article  CAS  PubMed  Google Scholar 

  • Gillece P, Luz JM, Lennarz WJ, de La Cruz FJ, Romisch K (1999) Export of a cysteinefree misfolded secretory protein from the endoplasmic reticulumfor degradation requires interaction with protein disulfide isomerase. J Cell Biol 147:1443–1456

    Article  CAS  PubMed  Google Scholar 

  • Grandea AG 3rd, Androlewicz MJ, Athwal RS, Geraghty DE, Spies T (1995) Dependence of peptide binding by MHC class I molecules on their interaction with TAP. Science 270:105–108

    CAS  PubMed  Google Scholar 

  • Gromme M, van der Valk R, Sliedregt K, Vernie L, Liskamp R, Hammerling G, Koopmann JO, Momburg F, Neefjes J (1997) The rational design of TAP inhibitors using peptide substrate modifications and peptidomimetics. Eur J Immunol 27:898–904

    CAS  PubMed  Google Scholar 

  • Gu YQ, Walling LL (2002) Identification of residues critical for activity of the wound-induced leucine aminopeptidase(LAP-A) of tomato. Eur J Biochem 269:1630–1640

    CAS  PubMed  Google Scholar 

  • Hampton RY (2002) ER-associated degradation in protein quality control and cellular regulation. Curr Opin Cell Biol 14:476–482

    Article  CAS  PubMed  Google Scholar 

  • Heemels MT, Schumacher TN, Wonigeit K, Ploegh HL (1993) Peptide translocation by variants of the transporter associated with antigen processing. Science 262:2059–2063

    CAS  PubMed  Google Scholar 

  • Hewitt EW, Gupta SS, Lehner PJ (2001) The human cytomegalovirus gene product US6 inhibits ATP binding by TAP. EMBO J 20:387–396

    Article  CAS  PubMed  Google Scholar 

  • Hui M, Hui KS (2003) Neuron-specific aminopeptidase and puromycin-sensitive aminopeptidase in rat brain development. Neurochem Res 28:855–860

    Article  CAS  PubMed  Google Scholar 

  • Kakuta H, Koiso Y, Nagasawa K, Hashimoto Y (2003) Fluorescent bioprobes for visualization of puromycin-sensitive aminopeptidase in living cells. Bioorg Med Chem Lett 13:83–86

    Article  CAS  PubMed  Google Scholar 

  • Kane RC, Bross PF, Farrell AT, Pazdur R (2003) Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 8:508–513

    Article  PubMed  Google Scholar 

  • Kelly A, Powis SH, Kerr LA, Mockridge I, Elliott T, Bastin J, Uchanska-Ziegler B, Ziegler A, Trowsdale J, Townsend A (1992) Assembly and function of the two ABC transporter proteins encoded in the human major histocompatibility complex. Nature 355:641–644

    Article  CAS  PubMed  Google Scholar 

  • Klein I, Sarkadi B, Varadi A (1999) An inventory of the human ABC proteins. Biochim Biophys Acta 1461:237–262

    CAS  PubMed  Google Scholar 

  • Kondagunta GV, Drucker B, Schwartz L, Bacik J, Marion S, Russo P, Mazumdar M, Motzer RJ (2004) Phase II trial of bortezomib for patients with advanced renal cell carcinoma. J Clin Oncol 22:3720–3725

    Article  CAS  PubMed  Google Scholar 

  • Koopmann JO, Albring J, Huter E, Bulbuc N, Spee P, Neefjes J, Hammerling GJ, Momburg F (2000) Export of antigenic peptides from the endoplasmic reticulum intersects with retrograde protein translocation through the Sec61p channel. Immunity 13:117–127

    Article  CAS  PubMed  Google Scholar 

  • Koopmann JO, Post M, Neefjes JJ, Hammerling GJ, Momburg F (1996) Translocation of long peptides by transporters associated with antigen processing (TAP). Eur J Immunol 26:1720–1728

    CAS  PubMed  Google Scholar 

  • Koppers-Lalic D, Rychlowski M, van Leeuwen D, Rijsewijk FA, Ressing ME, Neefjes JJ, Bienkowska-Szewczyk K, Wiertz EJ (2003) Bovine herpesvirus 1 interferes with TAP-dependent peptide transport and intracellular trafficking of MHC class I molecules in human cells. Arch Virol 148:2023–2037

    Article  CAS  PubMed  Google Scholar 

  • Kuo LY, Hwang GY, Lai YJ, Yang SL, Lin LL (2003) Overexpression, purification, characterization of the recombinant leucine aminopeptidase II of Bacillus stearother-mophilus. Curr Microbiol 47:40–45

    CAS  PubMed  Google Scholar 

  • Lammert E, Arnold D, Nijenhuis M, Momburg F, Hammerling GJ, Brunner J, Stevanovic S, Rammensee HG, Schild H (1997a) The endoplasmic reticulum-resident stress protein gp96 binds peptides translocated by TAP. Eur J Immunol 27:923–927

    CAS  PubMed  Google Scholar 

  • Lammert E, Stevanovic S, Brunner J, Rammensee HG, Schild H (1997b) Protein disulfide isomerase is the dominant acceptor for peptides translocated into the endoplasmic reticulum. Eur J Immunol 27:1685–1690

    CAS  PubMed  Google Scholar 

  • Millican PE, Kenny AJ, Turner AJ (1991) Purification and properties of a neurotensin-degrading endopeptidase from pig brain. Biochem J 276:583–591

    CAS  PubMed  Google Scholar 

  • Momburg F, Roelse J, Hammerling GJ, Neefjes JJ (1994a) Peptide size selection by the major histocompatibility complex-encoded peptide transporter. J Exp Med 179:1613–1623

    Article  CAS  PubMed  Google Scholar 

  • Momburg F, Roelse J, Howard JC, Butcher GW, Hammerling GJ, Neefjes JJ (1994b) Selectivity of MHC-encoded peptide transporters from human, mouse and rat. Nature 367:648–651

    Article  CAS  PubMed  Google Scholar 

  • Neefjes JJ, Momburg F, Hammerling GJ (1993) Selective and ATP-dependent translocation of peptides by the MHC-encoded transporter. Science 261:769–771

    CAS  PubMed  Google Scholar 

  • Neefjes JJ, Ploegh HL (1988) 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

    CAS  PubMed  Google Scholar 

  • Neisig A, Roelse J, Sijts AJ, Ossendorp F, Feltkamp MC, Kast WM, Melief CJ, Neefjes JJ (1995) Major differences in transporter associatedwith antigen presentation (TAP)-dependent translocation of MHC class I-presentable peptides and the effect of flanking sequences. J Immunol 154:1273–1279

    CAS  PubMed  Google Scholar 

  • Neisig A, Wubbolts R, Zang X, Melief C, Neefjes J (1996) Allele-specific differences in the interaction of MHC class I molecules with transporters associated with antigen processing. J Immunol 156:3196–3206

    CAS  PubMed  Google Scholar 

  • Nishimura C, Suzuki H, Tanaka N, Yamaguchi H (1989) Bleomycinhydrolase is a unique thiol aminopeptidase. Biochem Biophys Res Commun 163:788–796

    CAS  PubMed  Google Scholar 

  • Nishimura C, Tanaka N, Suzuki H (1987) Purification of bleomycin hydrolase with a monoclonal antibody and its characterization. Biochemistry 26:1574–1578

    Article  CAS  PubMed  Google Scholar 

  • Ortmann B, Copeman J, Lehner PJ, Sadasivan B, Herberg JA, Grandea AG, Riddell SR, Tampe R, Spies T, Trowsdale J, Cresswell P (1997) A critical role for tapasin in the assembly and function of multimeric MHC class I-TAP complexes. Science 277:1306–1309

    Article  CAS  PubMed  Google Scholar 

  • Papandreou CN, Logothetis CJ (2004) Bortezomib as a potential treatment for prostate cancer. Cancer Res 64:5036–5043

    Article  CAS  PubMed  Google Scholar 

  • Princiotta MF, Finzi D, Qian SB, Gibbs J, Schuchmann S, Buttgereit F, Bennink JR, Yewdell JW(2003) Quantitating protein synthesis, degradation, endogenous antigen processing. Immunity 18:343–354

    Article  CAS  PubMed  Google Scholar 

  • Rammensee HG, Falk K, Rotzschke O (1993) Peptides naturally presented by MHC class I molecules. Annu Rev Immunol 11:213–244

    Article  CAS  PubMed  Google Scholar 

  • Reits E, Griekspoor A, Neijssen J, Groothuis T, Jalink K, van Veelen P, Janssen H, Calafat J, Drijfhout JW, Neefjes J (2003) Peptide diffusion, protection, degradation in nuclear and cytoplasmic compartments before antigen presentation by MHC class I. Immunity 18:97–108

    Article  CAS  PubMed  Google Scholar 

  • Reits E, Neijssen J, Herberts C, Benckhuijsen W, Janssen L, Drijfhout JW, Neefjes J (2004) A major role for TPPII in trimming proteasomal degradation products for MHC class I antigen presentation. Immunity 20:495–506

    Article  CAS  PubMed  Google Scholar 

  • Reits EA, Griekspoor AC, Neefjes J (2000a) How does TAP pump peptides? Insights from DNA repair and traffic ATPases. Immunol Today 21:598–600

    Article  CAS  PubMed  Google Scholar 

  • Reits EA, Neefjes JJ (2001) From fixed to FRAP: measuring protein mobility and activity in living cells. Nat Cell Biol 3:E145–E147

    Article  CAS  PubMed  Google Scholar 

  • Reits EA, Vos JC, Gromme M, Neefjes J (2000b) The major substrates for TAP in vivo are derived from newly synthesized proteins. Nature 404:774–778

    Article  CAS  PubMed  Google Scholar 

  • Renn SC, Tomkinson B, Taghert PH (1998) Characterization and cloning of tripeptidyl peptidase II from the fruit fly, Drosophila melanogaster. J Biol Chem 273:19173–19182

    Article  CAS  PubMed  Google Scholar 

  • Roelse J, Gromme M, Momburg F, Hammerling G, Neefjes J (1994) Trimming of TAP-translocated peptides in the endoplasmic reticulum and in the cytosol during recycling. J Exp Med 180:1591–1597

    Article  CAS  PubMed  Google Scholar 

  • Saric T, Chang SC, Hattori A, York IA, Markant S, Rock KL, Tsujimoto M, Goldberg AL (2002) An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nat Immunol 3:1169–1176

    Article  CAS  PubMed  Google Scholar 

  • Saric T, Graef CI, Goldberg AL (2004) Pathway for degradation of peptides generated by proteasomes: a key role for thimet oligopeptidase and other metallopeptidases. J Biol Chem 279:46273–46732

    Article  Google Scholar 

  • Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404:770–774

    Article  CAS  PubMed  Google Scholar 

  • Schumacher TN, Kantesaria DV, Heemels MT, Ashton-Rickardt PG, Shepherd JC, Fruh K, Yang Y, Peterson PA, Tonegawa S, Ploegh HL (1994) Peptide length andsequence specificity of the mouse TAP1/TAP2 translocator. J Exp Med 179:533–540

    Article  CAS  PubMed  Google Scholar 

  • Sebti SM, DeLeon JC, Lazo JS (1987) Purification, characterization, amino acid composition of rabbit pulmonary bleomycin hydrolase. Biochemistry 26:4213–4219

    CAS  PubMed  Google Scholar 

  • Sebti SM, Lazo JS (1987) Separation of the protective enzyme bleomycin hydrolase from rabbit pulmonary aminopeptidases. Biochemistry 26:432–437

    CAS  PubMed  Google Scholar 

  • Serwold T, Gonzalez F, Kim J, Jacob R, Shastri N (2002) ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum. Nature 419:480–483

    Article  CAS  PubMed  Google Scholar 

  • Shepherd JC, Schumacher TN, Ashton-Rickardt PG, Imaeda S, Ploegh HL, Janeway CA, Jr, Tonegawa S (1993) TAP1-dependent peptide translocation in vitro is ATP dependent and peptide selective. Cell 74:577–584

    Article  CAS  PubMed  Google Scholar 

  • Spee P, Neefjes J (1997) TAP-translocated peptides specifically bind proteins in the endoplasmic reticulum, including gp96, protein disulfide isomerase and calreticulin. Eur J Immunol 27:2441–2449

    CAS  PubMed  Google Scholar 

  • Spee P, Subjeck J, Neefjes J (1999) Identification of novel peptide binding proteins in the endoplasmic reticulum: ERp72, calnexin, grp170. Biochemistry 38:10559–10566

    Article  CAS  PubMed  Google Scholar 

  • Suh WK, Cohen-Doyle MF, Fruh K, Wang K, Peterson PA, Williams DB (1994) Interaction of MHC class I molecules with the transporter associated with antigen processing. Science 264:1322–1326

    CAS  PubMed  Google Scholar 

  • Thompson MW, Govindaswami M, Hersh LB (2003) Mutation of active site residues of the puromycin-sensitive aminopeptidase: conversion of the enzyme into a catalytically inactive binding protein. Arch Biochem Biophys 413:236–242

    Article  CAS  PubMed  Google Scholar 

  • Thompson MW, Hersh LB (2003) Analysis of conserved residues of the human puromycin-sensitive aminopeptidase. Peptides 24:1359–1365

    Article  CAS  PubMed  Google Scholar 

  • Townsend A, Ohlen C, Bastin J, Ljunggren HG, Foster L, Karre K (1989) Association of class Imajor histocompatibility heavy and light chains induced by viral peptides. Nature 340:443–448

    Article  CAS  PubMed  Google Scholar 

  • Vos JC, Reits EA, Wojcik-Jacobs E, Neefjes J (2000) Head-head/tail-tail relative orientation of the pore-forming domains of the heterodimeric ABC transporter TAP. Curr Biol 10:1–7

    Article  CAS  PubMed  Google Scholar 

  • Vos JC, Spee P, Momburg F, Neefjes J (1999) Membrane topology and dimerization of the two subunits of the transporter associated with antigen processing reveal a three-domain structure. J Immunol 163:6679–6685

    CAS  PubMed  Google Scholar 

  • Yewdell JW (2001) Not such a dismal science: the economics of protein synthesis, folding, degradation and antigen processing. Trends Cell Biol 11:294–297

    Article  CAS  PubMed  Google Scholar 

  • Yewdell JW, Reits E, Neefjes J (2003) Making sense of mass destruction: quantitating MHC class I antigen presentation. Nat Rev Immunol 3:952–961

    Article  CAS  PubMed  Google Scholar 

  • Yewdell JW, Schubert U, Bennink JR (2001) At the crossroads of cell biology and immunology: DRiPs and other sources of peptide ligands for MHC class Imolecules. J Cell Sci 114:845–851

    CAS  PubMed  Google Scholar 

  • York IA, Chang SC, Saric T, Keys JA, Favreau JM, Goldberg AL, Rock KL (2002) The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8-9 residues. Nat Immunol 3:1177–1184

    Article  CAS  PubMed  Google Scholar 

  • York IA, Mo AX, Lemerise K, Zeng W, Shen Y, Abraham CR, Saric T, Goldberg AL, Rock KL (2003) The cytosolic endopeptidase, thimet oligopeptidase, destroys antigenic peptides and limits the extent of MHC class I antigen presentation. Immunity 18:429–440

    Article  CAS  PubMed  Google Scholar 

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Groothuis, T., Neefjes, J. (2006). The Ins and Outs of Intracellular Peptides and Antigen Presentation by MHC Class I Molecules. In: Wiertz, E., Kikkert, M. (eds) Dislocation and Degradation of Proteins from the Endoplasmic Reticulum. Current Topics in Microbiology and Immunology, vol 300. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-28007-3_6

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