title: Ubiquitination by March-I prevents MHC class II recycling and promotes MHC class II turnover in antigen-presenting cells.
abstract: MHC class II (MHC-II)-dependent antigen presentation by antigen-presenting cells (APCs) is carefully controlled to achieve specificity of immune responses; the regulated assembly and degradation of antigenic peptide-MHC-II complexes (pMHC-II) is one aspect of such control. In this study, we have examined the role of ubiquitination in regulating pMHC-II biosynthesis, endocytosis, recycling, and turnover in APCs. By using APCs obtained from MHC-II ubiquitination mutant mice, we find that whereas ubiquitination does not affect pMHC-II formation in dendritic cells (DCs), it does promote the subsequent degradation of newly synthesized pMHC-II. Acute activation of DCs or B cells terminates expression of the MHC-II E3 ubiquitin ligase March-I and prevents pMHC-II ubiquitination. Most importantly, this change results in very efficient pMHC-II recycling from the surface of DCs and B cells, thereby preventing targeting of internalized pMHC-II to lysosomes for degradation. Biochemical and functional assays confirmed that pMHC-II turnover is suppressed in MHC-II ubiquitin mutant DCs or by acute activation of wild-type DCs. These studies demonstrate that acute APC activation blocks the ubiquitin-dependent turnover of pMHC-II by promoting efficient pMHC-II recycling and preventing lysosomal targeting of internalized pMHC-II, thereby enhancing pMHC-II stability for efficient antigen presentation to CD4 T cells.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Kyung-Jin
authors.initials: KJ
authors.lastname: Cho
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Even
authors.initials: E
authors.lastname: Walseng
authors.affiliation: Laboratory of Integrative Infection Immunity, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishido
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; paul.roche@nih.gov.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Roche
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000166:cytology*; D001402:B-Lymphocytes / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D003713:Dendritic Cells / Q000166:cytology; D004705:Endocytosis; D000949:Histocompatibility Antigens Class II / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000737:chemistry; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000737:chemistry; D025801:Ubiquitin / Q000737:chemistry*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
chemical_list: D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; D010455:Peptides; D025801:Ubiquitin; C545340:MARCH1 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: MHC class II; March-I; antigen processing and presentation; recycling; ubiquitination