ISOLATION OF LOW-MOLECULAR-MASS POLYPEPTIDE COMPLEMENTARY-DNA CLONES FROM PRIMITIVE VERTEBRATES - IMPLICATIONS FOR THE ORIGIN OF MHC CLASS I-RESTRICTED ANTIGEN PRESENTATION

Proteasomes are the multisubunit proteases thought to be involved in t he generation of peptides presented by MHC class I molecules. When cel ls are stimulated with IFN-gamma, two MHC-encoded subunits, LMP2 and L MP7, are incorporated into the proteasomal complex, presumably by disp lacing the housekeeping subunits, designated Y and X, respectively, Th ese changes in the subunit composition appear to facilitate class I-me diated Ag presentation, presumably by altering the cleavage specificit ies of the proteasome, Here we show that the cartilaginous fish, the m ost primitive class of vertebrates in which the MHC has been identifie d, have both LMP7 and X genes, Interestingly, nurse sharks, a member o f the cartilaginous fish, appear to have two LMP7 genes, one encoding a typical LMP7 subunit and the other encoding a less typical one. In c ontrast, only cDNA clones with residues characteristic of X were ident ified in hagfishes and lampreys, the two extant members of the jawless fish in which no MHC has been identified, Pairwise amino acid sequenc e comparison and phylogenetic tree analysis showed that the subunits e ncoded by these clones were nearly equidistant from LMP7 and X, sugges ting that the LMP7 gene might have emerged after the appearance of the jawless fish. Sequence comparison of the LMP7 and X/X-like subunits i solated from various vertebrate species showed that, unlike the X/X-li ke subunit, the LMP7 subunit displays a striking interspecies sequence variability in the vicinity of its catalytic site.