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J. Exp. Med.,
Volume 187, Number 10, May 18, 1998 1641-1646
By
From the * Zentrum für Experimentelle Medizin (ZEM), Institut für Biochemie, Charité, Humboldt
Universität zu Berlin, 10117 Berlin, Germany; and the Proteasomes generate peptides bound by major histocompatibility complex (MHC) class I
molecules. Avoiding proteasome inhibitors, which in most cases do not distinguish between
individual active sites within the cell, we used a molecular genetic approach that allowed for
the first time the in vivo analysis of defined proteasomal active sites with regard to their significance for antigen processing. Functional elimination of the Max von Pettenkofer Institut, 80336 München, Germany
/low molecular weight protein
(LMP) 2 sites by substitution with a mutated inactive LMP2 T1A subunit results in reduced cell
surface expression of the MHC class I H-2Ld and H-2Dd molecules. Surface levels of H-2Ld and
H-2Dd molecules were restored by external loading with peptides. However, as a result of the
active site mutation, MHC class I presentation of a 9-mer peptide derived from a protein of
murine cytomegalovirus was enhanced about three- to fivefold. Our experiments provide evidence that the /LMP2 active site elimination limits the processing and presentation of several
peptides, but may be, nonetheless, beneficial for the generation and presentation of others.
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