Beyond the proteasome: trimming, degradation and generation of MHC class I ligands by auxiliary proteases.
The proteasome is now recognized to be implicated in the generation of the vast majority of MHC class I ligands. Moreover, it is probably the only cytosolic protease generating their carboxyterminals. However, solid evidence documents a role of additional and only partly identified proteases in MHC class I antigen processing. Cytosolic tripeptidyl peptidase (TTP II) may be able to carry out some functions normally ascribed to the proteasome, including that of generating antigenic peptides. Several cytosolic enzymes, including bleomycin hydrolase (BH) and puromycin-sensitive aminopeptidase (PSA), but especially the IFNgamma-inducible leucyl aminopeptidase (LAP), can trim the aminoterminal ends of class I ligands. The vast majority of cytosolic peptides is degraded, a process likely to limit antigen presentation, in which thimet oligopeptidase (TOP) may play an important role. Proteolytic activity in the secretory pathway, though much more limited than in the cytosol, also contributes to class I antigen presentation. Signal peptide fragments and peptides at the carboxyterminal end of various proteins targeted to the endoplasmic reticulum can be highly efficient TAP-independent class I ligands. However, an as yet unidentified luminal trimming aminopeptidase may eventually turn out to play the most important role for class I ligand generation in the secretory pathway. Defining the extent of the involvement of cytosolic and luminal peptidases in class I antigen processing will be a challenging task for the future.
INSERM U25, 161 Rue de Sèvres, 75743 Paris, Cedex 15, France.
Loredana
L
Saveanu
Doriana
D
Fruci
Peter
P
van Endert
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000502:physiology*; D003600:Cytosol / Q000201:enzymology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009097:Multienzyme Complexes / Q000502:physiology*; D010455:Peptides / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D000941:Antigens; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D009097:Multienzyme Complexes; D010455:Peptides; C073119:TAP1 protein, human; C071692:TAP2 protein, human; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex