title: Inhibition of MHC class II expression and immune responses by c-MIR.
abstract: We previously reported a novel E3 ubiquitin ligase (E3), designated as c-MIR, which targets B7-2 to lysosomal degradation and down-regulates the B7-2 surface expression through ubiquitination of its cytoplasmic tail. B7-2 is well known as a costimulatory molecule for Ag presentation, suggesting that the manipulation of c-MIR expression modulates immune responses in vivo. To examine this hypothesis, we generated genetically modified mice in which c-MIR was expressed under an invariant chain (Ii) promoter. Dendritic cells derived from genetically engineered mice showed low ability to present Ags. In addition, these mice showed resistance to the onset of experimental autoimmune encephalomyelitis and an impaired development of CD4 T cells in the thymus and the periphery. These findings led us to conclude that MHC class II (MHC II) is an additional target for c-MIR. Indeed, forced expression of c-MIR in several B cell lines down-regulated the surface expression of MHC II, and down-regulation was found to depend on the presence of a single lysine residue in the cytoplasmic tail of the I-A beta-chain. In a reconstitution system using 293T cells, we found that the lysine residue at position 225 in the I-A beta-chain was ubiquitinated by c-MIR. To our knowledge, c-MIR is the first example of an E3 that is capable of inhibiting MHC II expression. Our findings suggest that c-MIR might potently regulate immune responses in vivo.
authors.affiliation: Laboratory for Infectious Immunity, The Institute of Physical and Chemical Research (RIKEN), Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Ohmura-Hoshino
authors.forename: Yohei
authors.initials: Y
authors.lastname: Matsuki
authors.forename: Masami
authors.initials: M
authors.lastname: Aoki
authors.forename: Eiji
authors.initials: E
authors.lastname: Goto
authors.forename: Mari
authors.initials: M
authors.lastname: Mito
authors.forename: Mika
authors.initials: M
authors.lastname: Uematsu
authors.forename: Terutaka
authors.initials: T
authors.lastname: Kakiuchi
authors.forename: Hak
authors.initials: H
authors.lastname: Hotta
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishido
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003433:Crosses, Genetic; D003593:Cytoplasm / Q000201:enzymology / Q000276:immunology; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D004705:Endocytosis / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000378:metabolism; D008239:Lysine / Q000737:chemistry / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D021122:Protein Subunits / Q000737:chemistry / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D051940:B7-2 Antigen; D000949:Histocompatibility Antigens Class II; C111389:I-Ad antigen; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D021122:Protein Subunits; D025801:Ubiquitin; C403126:MYLIP protein, human; D044767:Ubiquitin-Protein Ligases; D008239:Lysine