Proteolysis of the class II-associated invariant chain generates a peptide binding site in intracellular HLA-DR molecules. Proc. Natl. Acad. Sci. USA. 1991. 88: 3150-3154.

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 αß dimer on the cell surface, however the I chain is removed from the intracellular αßI complex by a mechanism thought to involve proteolysis . In this report, we show that treatment of purified αßI 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 αß dimers are released from αßI. Although αßI fails to bind an immunogenic peptide, the released αß 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 αßI early during intracellular transport and demonstrate that proteolysis is likely to be the in vivo mechanism of I chain removal.