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J Biol Chem, Vol. 273, Issue 30, 18734-18742, July 24, 1998
Can Stimulate Post-proteasomal Trimming of the
N Terminus of an Antigenic Peptide by Inducing Leucine
Aminopeptidase
, and
From the Department of Cell Biology, Harvard Medical School,
Boston, Massachusetts 02115 and the Most antigenic peptides presented on major
histocompatibility complex class I molecules are generated during
protein breakdown by proteasomes, whose specificity is altered by
interferon- Department of
Pathology, University of Massachusetts Medical Center,
Worchester, Massachusetts 01655
(IFN-). When extended versions of the
ovalbumin-derived epitope SIINFEKL are expressed in vivo,
the correct C terminus is generated by proteasomal cleavage, but
distinct cytosolic protease(s) generate its N terminus. To identify the
other protease(s) involved in antigen processing, we incubated soluble
extracts of HeLa cells with the 11-mer QLESIINFEKL, which
in vivo is processed to the antigenic 8-mer (SIINFEKL) by a
proteasome-independent pathway. This 11-mer was converted to the 9-mer
by sequential removal of the N-terminal residues, but surprisingly the
extract showed little or no endopeptidase or carboxypeptidase activity
against this precursor. After treatment of cells with IFN-, this
N-terminal trimming was severalfold faster and proceeded to the
antigenic 8-mer. The IFN-treated cells also showed greater
aminopeptidase activity against many model fluorogenic substrates. Upon
extract fractionation, three bestatin-sensitive aminopeptidase peaks
were detected. One was induced by IFN- and was identified
immunologically as leucine aminopeptidase (LAP). Purified LAP, like the
extracts of IFN--treated cells, processed the 11-mer peptide to
SIINFEKL. Thus, IFN- not only promotes proteasomal cleavages that
determine the C termini of antigenic peptides, but also can stimulate
formation of their N termini by inducing LAP. This enzyme appears to
catalyze the trimming of the N terminus of this and presumably other
proteasome-derived precursors. Thus, susceptibility to LAP may be an
important influence on the generation on immunodominant epitopes.
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