2005 Fiscal Year Final Research Report Summary
Functional analysis of a novel E3 ubiquitin ligase, c-MIR
| Project/Area Number |
16590405
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | RIKEN |
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Principal Investigator |
ISHICO Satoshi RIKEN, Infectious Immunity Team, Team Leader, 感染免疫応答研究チーム, チームリーダー (10273781)
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| Project Period (FY) |
2004 – 2005
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| Keywords | ubiquitin / antigen presentation / ubiquitin ligase / MHC Class II / endocytosis / B7-2 / transgenic mouse / immunosuppressor |
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| Research Abstract |
We previously reported a novel E3 ubiquitin ligase (E3)^4, 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 co-stimulatory molecule for antigen 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 (li) promoter. Dendritic cells (DCs) derived from genetically engineered mice showed low ability to present antigens. In addition, these mice showed resistance to the onset of experimental autoimmune encephalomyelitis (EAE) 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 downregulation was found to depend on the presence of a single lysine residue in the cytoplasmic tail of the I-A β chain. In a reconstitution system using 293T cells, we found that the lysine residue at position 225 in the I-A β 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.
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[Journal Article] A novel family of membrane-bound E3 ubiquitin ligases2006
Author(s)
Ohmura-Hoshino, M., Goto, E., Matsuki, Y., Aoki, M., Mito, M., Uematsu, M., Hotta, H., Ishido, S.
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Journal Title
The Journal of Biochemistry (In press)
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Inhibition of MHC class II expression and immune responses by c-MIR12006
Author(s)
Ohmura-Hoshino, M., Matsuki, Y., Aoki, M., Goto, E., Mito, M., M.Uematsu, Kakiuchi, T., Hotta, H., Ishido, S.
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Journal Title
The Journal of Immunology (In press)
Description
「研究成果報告書概要(和文)」より
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[Journal Article] A novel family of membrane-bound E3 ubiquitin ligases2006
Author(s)
Ohmura-Hoshino M., Goto, E., Matsuki, Y., Aoki, M., Mito, M., Uematsu, M., Hotta, H., Ishido, S.
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Journal Title
The Journal of Biochemistry (in Press)
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Inhibition of MHC class II expression and immune responses by c-MIR12006
Author(s)
Ohmura-Hoshino, M., Matsuki, Y., Aoki, M., Goto, E., Mito, M., M.Uematsu, Kakiuchi, T., Hotta H., Ishido S.
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Journal Title
The Journal of Immunology (in Press)
Description
「研究成果報告書概要(欧文)」より
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