Mechanisms of MHC class I--restricted antigen processing.
Classical class I molecules assemble in the endoplasmic reticulum (ER) with peptides mostly generated from cytosolic proteins by the proteasome. The activity of the proteasome can be modulated by a variety of accessory protein complexes. A subset of the proteasome beta-subunits (LMP2, LMP7, and MECL-1) and one of the accessory complexes, PA28, are upregulated by gamma-interferon and affect the generation of peptides to promote more efficient antigen recognition. The peptides are translocated into the ER by the transporter associated with antigen processing (TAP). A transient complex containing a class I heavy chain-beta 2 microglobulin (beta 2 m) dimer is assembled onto the TAP molecule by successive interactions with the ER chaperones calnexin and calreticulin and a specialized molecule, tapasin. Peptide binding releases the class I-beta 2 m dimer for transport to the cell surface, while lack of binding results in proteasome-mediated degradation. The products of certain nonclassical MHC-linked class I genes bind peptides in a similar way. A homologous set of beta 2 m-associated membrane glycoproteins, the CD1 molecules, appears to bind lipid-based ligands within the endocytic pathway.
Pamer
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Department of Internal Medicine and Section of Immunobiology, Yale University School of Medicine, Howard Hughes Medical Institute, New Haven, CT 06510, USA. eric.pamer@yale.edu
Cresswell
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P
D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D017951:Antigen Presentation / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000502:physiology; D019281:Dimerization; D004721:Endoplasmic Reticulum / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006801:Humans; D009097:Multienzyme Complexes / Q000502:physiology; D046988:Proteasome Endopeptidase Complex; D001613:beta 2-Microglobulin / Q000502:physiology
D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; D001613:beta 2-Microglobulin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex