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De Gassart, A, Camosseto, V, Thibodeau, J, Ceppi, M, Catalan, N, Pierre, P and Gatti, E (2008) MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation. Proc. Natl. Acad. Sci. U.S.A. 105:3491-6
In response to Toll-like receptor ligands, dendritic cells (DCs) dramatically enhance their antigen presentation capacity by stabilizing at the cell-surface MHC II molecules. We demonstrate here that, in human monocyte-derived DCs, the RING-CH ubiquitin E3 ligase, membrane-associated RING-CH I (MARCH I), promotes the ubiquitination of the HLA-DR beta-chain. Thus, in nonactivated DCs, MARCH I induces the surface internalization of mature HLA-DR complexes, therefore reducing their stability and levels. We further demonstrate that the maturation-dependent down-regulation of MARCH I is a key event in MHC class II up-regulation at the surface of LPS-activated DCs. MARCH I is, therefore, a major regulator of HLA-DR traffic, and its loss contributes to the acquisition of the potent immunostimulatory properties of mature human DCs.
Antigens, Surface; Biological Transport; Cells, Cultured; Dendritic Cells/immunology; Down-Regulation/genetics; Endocytosis; HLA-DR Antigens/metabolism; Histocompatibility Antigens Class II/metabolism; Humans; Lipopolysaccharides/pharmacology; Ubiquitin-Protein Ligases/genetics