Potential immunocompetence of proteolytic fragments produced by proteasomes before evolution of the vertebrate immune system.
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 gamma induction in vivo or addition of recombinant proteasome activator 28alpha 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.
Niedermann
G
G
Max-Planck-Institut für Immunbiologie, 79108 Freiburg, Germany.
Grimm
R
R
Geier
E
E
Maurer
M
M
Realini
C
C
Gartmann
C
C
Soll
J
J
Omura
S
S
Rechsteiner
M C
MC
Baumeister
W
W
Eichmann
K
K
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007121:Immunocompetence; D007371:Interferon-gamma / Q000096:biosynthesis; D008024:Ligands; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011817:Rabbits
D015395:Histocompatibility Antigens Class I; D008024:Ligands; D009097:Multienzyme Complexes; D010446:Peptide Fragments; C067713:lactacystin; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine