The DMalpha and DMbeta chain cooperate in the oxidation and folding of HLA-DM.

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 DMalpha and beta-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, DMalphabeta ER exit. However, glycosylation of DMalpha N15 is required for oxidation of the alpha-chain. The DMalpha and beta-chains direct each others fate: single DMalpha chains cannot fully oxidize without DMbeta, while DMbeta forms disulfide-linked homodimers without DMalpha. Correct oxidation and subsequent ER egress depend on the unique DMbeta 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.