Efficient MHC Class I-Independent Amino-Terminal Trimming of Epitope Precursor Peptides in the Endoplasmic Reticulum

• Published in: Immunity (Cambridge, Mass.) Vol. 15; no. 3; pp. 467 - 476
• Main Authors: Fruci, Doriana, Niedermann, Gabriele, Butler, Richard H, van Endert, Peter M
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2001
• Subjects: Adenosine Triphosphate - pharmacology; ATP-Binding Cassette Sub-Family B Member 2; ATP-Binding Cassette Transporters - physiology; Cell Line; Endoplasmic Reticulum - metabolism; Epitopes; histocompatibility antigen HLA; Histocompatibility Antigens Class I - physiology; HLA-A2 Antigen - metabolism; Humans; Metalloendopeptidases - physiology; Microsomes - metabolism; Protein Precursors - metabolism
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/S1074-7613(01)00203-5

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.