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.
Roche
P A
PA
Department of Microbiology and Immunology, Duke University Medical Center, Durham, NC 27710.
Cresswell
P
P
D000938:Antigen-Presenting Cells / Q000378:metabolism; D001665:Binding Sites; D002401:Cathepsin B / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D015180:Electrophoresis, Gel, Two-Dimensional; D006684:HLA-DR Antigens / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D013329:Structure-Activity Relationship
D006684:HLA-DR Antigens; D010455:Peptides; D002401:Cathepsin B