title: Internalizing MHC class II-peptide complexes are ubiquitinated in early endosomes and targeted for lysosomal degradation.
abstract: As sentinels of the immune system, dendritic cells (DCs) continuously generate and turnover antigenic peptide-MHC class II complexes (pMHC-II). pMHC-II generation is a complex process that involves many well-characterized MHC-II biosynthetic intermediates; however, the mechanisms leading to MHC-II turnover/degradation are poorly understood. We now show that pMHC-II complexes undergoing clathrin-independent endocytosis from the DC surface are efficiently ubiquitinated by the E3 ubiquitin ligase March-I in early endosomes, whereas biosynthetically immature MHC-II-Invariant chain (Ii) complexes are not. The inability of MHC-II-Ii to serve as a March-I substrate is a consequence of Ii sorting motifs that divert the MHC-II-Ii complex away from March-I(+) early endosomes. When these sorting motifs are mutated, or when clathrin-mediated endocytosis is inhibited, MHC-II-Ii complexes internalize by using a clathrin-independent endocytosis pathway and are now ubiquitinated as efficiently as pMHC-II complexes. These data show that the selective ubiquitination of internalizing surface pMHC-II in March-I(+) early endosomes promotes degradation of "old" pMHC-II and spares forms of MHC-II that have not yet loaded antigenic peptides or have not yet reached the DC surface.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Furuta
authors.forename: Even
authors.initials: E
authors.lastname: Walseng
authors.forename: Paul A
authors.initials: PA
authors.lastname: Roche
mesh_terms: D019921:Biotinylation; D003713:Dendritic Cells / Q000276:immunology*; D011992:Endosomes / Q000378:metabolism*; D005802:Genes, MHC Class II / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008247:Lysosomes / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D054875:Ubiquitination
chemical_list: D046912:Multiprotein Complexes; D010455:Peptides; D034741:RNA, Small Interfering