Efficient MHC class I-independent amino-terminal trimming of epitope precursor peptides in the endoplasmic reticulum.
MHC class I ligands are produced mainly by proteasomal proteolysis, in conjunction with an unknown extent of trimming by peptidases. Trimming of precursor peptides in the endoplasmic reticulum, a process postulated to be class I dependent, may substantially enhance the efficiency of antigen presentation. However, monitoring of luminal peptide processing has not so far been possible. Here we show that several precursor peptides with amino-terminal extensions are rapidly converted to HLA-A2 ligands by one or several highly efficient metallo-peptidases found on the outer surface of, but also within, microsomes. Surprisingly, luminal trimming is fully active in HLA class I- or TAP-deficient microsomes and precedes peptide association with HLA class I molecules. Trimmed peptides are rapidly depleted from, and become undetectable in, microsomes lacking the restricting class I molecules.
Fruci
D
D
Institut National de la Santé et de la Recherche Médicale, Unité 25, 75015 Paris, France.
Niedermann
G
G
Butler
R H
RH
van Endert
P M
PM
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000939:Epitopes; D015789:HLA-A2 Antigen / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006801:Humans; D008666:Metalloendopeptidases / Q000502:physiology; D008861:Microsomes / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000939:Epitopes; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D011498:Protein Precursors; C073119:TAP1 protein, human; D000255:Adenosine Triphosphate; D008666:Metalloendopeptidases