A previous study (see Further reading) showed that a conserved lysine residue in the β-chain of MHC class II molecules can be ubiquitylated. Because protein ubiquitylation is known to facilitate endocytosis and lysosomal degradation, Mellman and colleagues looked at the role of ubiquitylation of MHC class II molecules in controlling their cell-surface expression. By examining binding of a ubiquitin-specific antibody to immunoprecipitates of MHC class II molecules from immature DCs, they confirmed that the MHC class II β-chain can be modified with 1–5 ubiquitin monomers. In contrast to wild-type MHC class II molecules, a mutant MHC class II molecule in which the single lysine residue of the β-chain was replaced by an arginine residue (denoted MHC IIβ(K>R)) was not ubiquitylated when expressed in MHC-class-II-deficient DCs. Furthermore, the mutant MHC class II molecule was found mainly at the plasma membrane of immature DCs, in contrast to the mainly endosomal and lysosomal location of wild-type MHC class II molecules. Therefore, the lack of ubiquitylation correlates with cell-surface expression of MHC class II molecules.
Increased cell-surface expression could be the result of redistribution of MHC class II molecules to the cell surface or decreased clearance of these molecules from the cell surface. Few intracellular MHC class II molecules were detected in cells expressing MHC IIβ(K>R) compared with cells expressing wild-type MHC class II molecules, indicating that ubiquitylation correlates with endocytosis of MHC class II molecules from the cell surface. Also, in total, there were fourfold more MHC class II molecules in DCs expressing MHC IIβ(K>R) than in those expressing wild-type MHC class II molecules, indicating that endocytosis is linked to degradation. Treatment of DCs with an inhibitor of lysosomal proteolysis resulted in a significant increase in the number of MHC class II molecules.
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