Ubiquitylation downregulates the cell-surface expression of MHC class II molecules during the maturation of dendritic cells.
The unique status of mature dendritic cells (DCs) as 'professional' antigen-presenting cells that can stimulate naive T cells depends on their cell-surface expression of large amounts of co-stimulatory molecules and MHC class II molecules. Ira Mellman and colleagues describe a mechanism that provides an explanation for the upregulation of cell-surface expression of MHC class II molecules during the maturation of DCs.
A previous study (see Further reading) showed that a conserved lysine residue in the -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 -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 -chain was replaced by an arginine residue (denoted MHC II(KR)) 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 II(KR) 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 II(KR) 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.
The authors therefore suggest that DC maturation is associated with decreased ubiquitylation of MHC class II molecules, a process that results in an increase in the level of cell-surface expression as a consequence of decreased endocytosis and lysosomal degradation. Indeed, MHC class II molecules that were immunoprecipitated from mature DCs contained no detectable ubiquitin. Importantly, a constitutively ubiquitylated mutant MHC class II molecule continued to be internalized, and it retained a lysosomal localization even after the induction of DC maturation by lipopolysaccharide, thereby recapitulating the behaviour of MHC class II molecules in immature DCs. Further studies are required to determine how the ubiquitylation of MHC class II molecules is regulated.
Kirsty Minton
References
Shin, J. S. et al. Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination. Nature444, 115-118 (2 November 2006) | Article |
Ohmura-Hoshino, M. et al. Inhibition of MHC class II expression and immune responses by c-MIR. J. Immunol.177, 341–354 (2006) | PubMed |
-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 