Antigen Pong Thus teasomal degradation products from cells treated answers to these questions will have important implica with IFNy will be more likely to serve as MHC class I- tions for our understanding of how pathogens can evade presented antigens. somes are regulated by thei ting antigen processing,and with by inh more efficient vaccines efoaagBmonmpgceheoaritck8g proteasome,but the accessory 19S subunit is required for References When associated.the the 19mth the 20sot aom (ure 3b) associate with PA28(1IS subunit).thereby enhancing the he 20S and 265 proteasomes. antigen presentation units The 26S proteasome degrades ubiquitin-conjugated comp or o of proteaome ume function proteins.There are a number of enzymes that catalyse Lenz LL Dere B and Bevan MJ (196)Identification of an H2-M3 M3 I e h ubiquitin is thereby used as a tag to target the protein for Luckey CJ.Ki rto JAet al.(1998) MH entirely clea som antigens may require ubiquitir Pamer E and Cresswell P(1998)Mechanisms of MHC hslhstncted Pri Two major factors c nese cysteine protease are th n.Na369120-126 neutral pH,and are optimized to function in acidic endosomal compartments.The cystatin family of endo 82i-850 genous protease inhibi ace,and tha that talizatio Further Reading Cha The fu nd Disease 3rd edn.Current Biology-Garland. Concluding Remarks Although the last 10 vears hav ndous in in knowledge about the mechanisms of antigen processing C(997)Ca dereapctsremain unclear.One challenge ahead is to de rmine the role of different proce aor destroy Wolf PR and Ploegh HL(1995)How MHC class II molecules acquire dant cathepsins play in endosomal processing?The 6 ENCYCLOPEDIA OF LIFE SCIENCES/001 Nature Publishing Group/www.els.netThus, proteasomal degradation products from cells treated with IFNg will be more likely to serve as MHC class I￾presented antigens. Proteasomes are regulated by their association with various accessory protein complexes. The four stacked rings of a and b subunits together form the 20S proteasome, but the accessory 19S subunit is required for ubiquitin-dependent degradation. When associated, the 20S and 19S subunits form the 26S proteasome (Figure 3b). In addition to the 19S subunit, the 20S proteasome can also associate with PA28 (11S subunit), thereby enhancing the spectrum of produced peptides, which appears to improve antigen presentation. The PA28 subunit also has a heptameric configuration of alternating a and b subunits, and is inducible by IFNg. The 26S proteasome degrades ubiquitin-conjugated proteins. There are a number of enzymes that catalyse the covalent conjugation of ubiquitin to lysine residues within proteins via formation of isopeptide bonds. This leads to protein degradation by the proteasome, and ubiquitin is thereby used as a tag to target the protein for proteasomal degradation. The role for this pathway is not entirely clear, but some antigens may require ubiquitin conjugation for antigen processing. Regulation of processing in the MHC class II pathway is largely dependent on regulation of cathepsin activity in the endosomal compartment. Two major factors controlling activity of these cysteine proteases are the pH and the presence of endogenous cysteine protease inhibitors. Most cysteine proteases are unstable and have weak activity at neutral pH, and are optimized to function in acidic endosomal compartments. The cystatin family of endo￾genous protease inhibitors is found in the cytoplasm and extracellular space, and the main role of these inhibitors is to ensure that proteases that escape compartmentalization remain inactive. By these mechanisms, cathepsin activity is directed to the endosomal compartment where antigen processing and MHC class II loading occurs. Concluding Remarks Although the last 10 years have seen a tremendous increase in knowledge about the mechanisms of antigen processing, many aspects remain unclear. One challenge ahead is to determine the role of different proteases in both cytosolic and endosomal processing. Which cytosolic proteases, other than the proteasome, can generate or destroy antigenic peptides? What roles do the apparently redun￾dant cathepsins play in endosomal processing? The answers to these questions will have important implica￾tions for our understanding of how pathogens can evade the immune system by inhibiting antigen processing, and for development of more efficient vaccines. References Chapman HA (1998) Endosomal proteolysis andMHC class II function. Current Opinion in Immunology 10: 93–102. Coux O, Tanaka K and Goldberg AL (1996) Structure and functions of the 20S and 26S proteasomes. Annual Review ofBiochemistry 65: 801– 847. Glas R, Bogyo M, McMaster JS, Gaczynska M and Ploegh HL (1998) A proteolytic system that compensates for loss of proteasome function. Nature 392: 618–622. Jondal M, Schirmbeck R and Reimann J (1996) MHC class I restricted CTL responses to exogenous antigens. Immunity 5: 295–302. Lenz LL, Dere B and Bevan MJ (1996) Identification of an H2-M3 restricted Listeria epitope: implications for antigen presentation by M3. Immunity 5: 63–72. Luckey CJ, King GM, Marto JA et al. (1998) Proteasomes can either generate or destroy MHC class I epitopes: evidence for nonproteaso￾mal epitope generation in the cytosol. Journal ofImmunology 161: 112–121. Pamer E and Cresswell P (1998) Mechanisms of MHC class I-restricted antigen processing. Annual Review ofImmunology 16: 323–358. Prigozy TI, Sieling PA, Clemens D et al. (1997) The mannose receptor delivers lipoglycan antigens to endosomes for presentation to T cells by CD1b molecules. Immunity 6: 187–197. Tulp A, Verwoerd D, Dobberstein B, Ploegh HL and Pieters J (1994) Isolation and characterization of the intracellular MHC class II compartment. Nature 369: 120–126. Watts C (1997) Capture and processing of exogenous antigens for presentation on MHC molecules. Annual Review ofImmunology 15: 821–850. Further Reading Chapman HA (1998) Endosomal proteolysis andMHC class II function. Current Opinion in Immunology 10: 93–102. Janeway CA Jr and Travers P (1997) Immunobiology: The Immune System in Health and Disease, 3rd edn. Current Biology–Garland. London and New York. Pamer E and Cresswell P (1998) Mechanisms of MHC class I-restricted antigen processing. Annual Review ofImmunology 16: 323–358. Roitt IM (1997) Essential Immunology, 9th edn. Oxford: Blackwell Science. Watts C (1997) Capture and processing of exogenous antigens for presentation on MHC molecules. Annual Review ofImmunology 15: 821–850. Wolf PR and Ploegh HL (1995) How MHC class II molecules acquire peptide cargo: biosynthesis and trafficking through the endocytic pathway. Annual Review ofCell and Developmental Biology 11: 267– 306. Antigen Processing 6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net