PROTEOLYSIS OF THE CLASS-II-ASSOCIATED INVARIANT CHAIN GENERATES A PEPTIDE BINDING-SITE IN INTRACELLULAR HLA-DR MOLECULES

HLA-DR molecules are heterodimeric transmembrane glycoproteins that associate intracellularly with a polypeptide known as the invariant (I) chain. Shortly before expression of the HLA-DR alpha-beta-dimer on the cell surface, however, the I chain is removed from the intracellular alpha-beta-I complex by a mechanism thought to involve proteolysis. In this report, we show that treatment of purified alpha-beta-I with the cysteine proteinase cathepsin B results in the specific proteolysis of the HLA-DR-associated I chain in vitro. As a consequence of this, the I chain is removed and free alpha-beta-dimers are released from alpha-beta-I. Although alpha-beta-I fails to bind an immunogenic peptide, the released alpha-beta-dimers acquire the ability to bind the peptide after proteolysis of the I chain. These results suggest that the I chain inhibits immunogenic peptide binding to alpha-beta-I early during intracellular transport and demonstrate that proteolysis is likely to be the in vivo mechanism of I chain removal.