The DMα and DMβ Chain Cooperate in the Oxidation and Folding of HLA-DM

Abstract

HLA-DM (DM) is a heterodimeric MHC molecule that catalyzes the peptide loading of classical MHC class II molecules in the endosomal/lysosomal compartments of APCs. Although the function of DM is well-established, little is known about how DMα and β-chains fold, oxidize, and form a complex in the endoplasmic reticulum (ER). In this study, we show that glycosylation promotes, but is not essential for, DMαβ ER exit. However, glycosylation of DMα N15 is required for oxidation of the α-chain. The DMα and β-chains direct each others fate: single DMα chains cannot fully oxidize without DMβ, while DMβ forms disulfide-linked homodimers without DMα. Correct oxidation and subsequent ER egress depend on the unique DMβ C25 and C35 residues. This suggests that the C25-C35 disulfide bond in the peptide-binding domain overcomes the need for stabilizing peptides required by other MHC molecules.