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From the * Max-Planck-Institut für Immunbiologie, 79108 Freiburg, Germany; To generate peptides for presentation by major histocompatibility complex (MHC) class I molecules to T lymphocytes, the immune system of vertebrates has recruited the proteasomes,
phylogenetically ancient multicatalytic high molecular weight endoproteases. We have previously shown that many of the proteolytic fragments generated by vertebrate proteasomes have
structural features in common with peptides eluted from MHC class I molecules, suggesting
that many MHC class I ligands are direct products of proteasomal proteolysis. Here, we report
that the processing of polypeptides by proteasomes is conserved in evolution, not only among
vertebrate species, but including invertebrate eukaryotes such as insects and yeast. Unexpectedly, we found that several high copy ligands of MHC class I molecules, in particular, self-ligands, are major products in digests of source polypeptides by invertebrate proteasomes. Moreover, many major dual cleavage peptides produced by invertebrate proteasomes have the length
and the NH2 and COOH termini preferred by MHC class I. Thus, the ability of proteasomes
to generate potentially immunocompetent peptides evolved well before the vertebrate immune system. We demonstrate with polypeptide substrates that interferon 
Hewlett-Packard
GmbH, 76337 Waldbronn, Germany; § Department of Biochemistry, University of Utah, Salt Lake
City, Utah 84123; 
Botanisches Institut, Universität Kiel, 24089 Kiel, Germany; ¶ The Kitasato
Institute, Tokyo 108, Japan; and ** Max-Planck-Institut für Biochemie, 82152 Martiensried,
Germany
induction in vivo or addition of recombinant proteasome activator 28
in vitro alters proteasomal proteolysis in such a
way that the generation of peptides with the structural features of MHC class I ligands is optimized. However, these changes are quantitative and do not confer qualitatively novel characteristics to proteasomal proteolysis. The data suggest that proteasomes may have influenced the
evolution of MHC class I molecules.
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