Protein degradation and the generation of MHC class I-presented peptides.
Over the past decade there has been considerable progress in understanding how MHC class I-presented peptides are generated. The emerging theme is that the immune system has not evolved its own specialized proteolytic mechanisms but instead utilizes the phylogenetically ancient catabolic pathways that continually turnover proteins in all cells. Three distinct proteolytic steps have now been defined in MHC class I antigen presentation. The first step is the degradation of proteins by the ubiquitin-proteasome pathway into oligopeptides that either are of the correct size for presentation or are extended on their amino-termini. In the second step, aminopeptidases trim N-extended precursors into peptides of the correct length to be presented on class I molecules. The third step involves the destruction of peptides by endo- and exopeptidases, which limits antigen presentation, but is important for preventing the accumulation of peptides and recycling them back to amino acids for protein synthesis or production of energy. The immune system has evolved several components that modify the activity of these ancient pathways in ways that enhance the generation of class I-presented peptides. These include catalytically active subunits of the proteasome, the PA28 proteasome activator, and leucine aminopeptidase, all of which are upregulated by interferon-gamma. In addition to these pathways that operate in all cells, dendritic cells and macrophages can also generate class I-presented peptides from proteins internalized from the extracellular fluids by degrading them in endocytic compartments or transferring them to the cyotosol for degradation by proteasomes.
Rock
Kenneth L
KL
Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
York
Ian A
IA
Saric
Tomo
T
Goldberg
Alfred L
AL
D000818:Animals; D017951:Antigen Presentation; D003546:Cysteine Endopeptidases / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D009097:Multienzyme Complexes / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; D011506:Proteins; D025801:Ubiquitin; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex