c-MIR, a Human E3 Ubiquitin Ligase, Is a Functional Homolog of Herpesvirus Proteins MIR1 and MIR2 and Has Similar Activity

Gotō, Eiji; Ishido, Satoshi; Sato, Yuya; Ohgimoto, Shinji; Ohgimoto, Kaori; Nagano-Fujii, Motoko; Hotta, Hak

doi:10.1074/jbc.m211285200

Cited by 145 publications

(188 citation statements)

References 34 publications

(51 reference statements)

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“…However, there is indirect evidence that c-MIR might be a physiological immune modulator in vivo. We previously showed that forced expression of c-MIR down-regulates the expression of B7-2 and that c-MIR is expressed in human monocyte-derived DCs (1). In this study, we showed that the expression of MHC II was significantly inhibited by c-MIR in APCs, and that c-MIR was moderately expressed in splenic macrophages and splenic DCs, which are physiological APCs in vivo.…”

Section: Discussionmentioning

confidence: 56%

“…As shown in the case of other families of E3, MIR family proteins also induce the ubiquitination through binding to target molecules (1). The lysine residues in the cytoplasmic tail of target molecules have been identified as the sites for ubiquitination by MIR family proteins.…”

Section: Inhibition Of Mhc Class II Expression and Immune Responses Bmentioning

confidence: 91%

“…P reviously we reported a novel E3 ubiquitin ligase (E3), designated c-MIR, which targets B7-2 to lysosomal degradation by ubiquitination of its cytoplasmic tail (1). c-MIR has been proposed to belong to a novel family of E3, designated as the modulator of immune recognition (MIR) 4 family, whose catalytic domain is a variant RING domain (RING-CH domain) (2)(3)(4).…”

Section: Inhibition Of Mhc Class II Expression and Immune Responses Bmentioning

confidence: 99%

“…c-MIR was found as a functional and structural homolog of KSHV MIR1 and MIR2 by searching the public databases (1). At present, its physiological function remains unknown.…”

Section: Inhibition Of Mhc Class II Expression and Immune Responses Bmentioning

confidence: 99%

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Inhibition of MHC Class II Expression and Immune Responses by c-MIR

Ohmura‐Hoshino

Matsuki

Aoki

et al. 2006

The Journal of Immunology

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124

118

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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 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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Section: Discussionmentioning

confidence: 56%

Section: Inhibition Of Mhc Class II Expression and Immune Responses Bmentioning

confidence: 91%

Section: Inhibition Of Mhc Class II Expression and Immune Responses Bmentioning

confidence: 99%

“…c-MIR was found as a functional and structural homolog of KSHV MIR1 and MIR2 by searching the public databases (1). At present, its physiological function remains unknown.…”

Section: Inhibition Of Mhc Class II Expression and Immune Responses Bmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of MHC Class II Expression and Immune Responses by c-MIR

Ohmura‐Hoshino

Matsuki

Aoki

et al. 2006

The Journal of Immunology

Self Cite

124

118

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“…As documented for the viral homologs, the replacement of the RING by the one of another E3s does not affect the function of MIR1 (59). Interestingly, MARCH9 retained full activity against MHC I molecules in the context of the MARCH1 RING domain (M1-9DIRT) whereas the chimeric molecules has lost most of its activity against MHC II molecules (Fig.…”

Section: Discussionmentioning

confidence: 91%

Autoregulation of MARCH1 Expression by Dimerization and Autoubiquitination

Bourgeois-Daigneault

Thibodeau

2012

The Journal of Immunology

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Some members of the membrane-associated RING-CH family of E3 ubiquitin ligases (MARCHs) are membrane-bound and target major players of the immune response. MARCH1 ubiquitinates and downregulates MHC class II expression in APCs. It is induced by IL-10 and despite a strong increase in mRNA expression in human primary monocytes, the protein remains hardly detectable. To gain insights into the posttranslational regulation of MARCH1, we investigated whether its expression is itself regulated by ubiquitination. Our results demonstrate that MARCH1 is ubiquitinated in transfected human cell lines. Polyubiquitin chain-specific Abs revealed the presence of K48-linked polyubiquitin chains. A mutant devoid of lysine residues in the N- and C-terminal regions was less ubiquitinated and had a prolonged half-life. Reduced ubiquitination was also observed for an inactive mutated form of the molecule (M1WI), suggesting that MARCH1 is capable of autoubiquitination. Immunoprecipitation and energy transfer experiments demonstrated that MARCH1 homodimerizes and also forms heterodimers with others family members. Coexpression of MARCH1 decreased the protein levels of the inactive M1WI, suggesting a transubiquitination process. Taken together, our results suggest that MARCH1 may regulate its own expression through dimerization and autoubiquitination.

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MEKK1: Dual Function as a Protein Kinase and a Ubiquitin Protein Ligase

Lu¹,

Hunter²

2007

Protein Degradation Series

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c-MIR, a Human E3 Ubiquitin Ligase, Is a Functional Homolog of Herpesvirus Proteins MIR1 and MIR2 and Has Similar Activity

Cited by 145 publications

References 34 publications

Inhibition of MHC Class II Expression and Immune Responses by c-MIR

Inhibition of MHC Class II Expression and Immune Responses by c-MIR

Autoregulation of MARCH1 Expression by Dimerization and Autoubiquitination

MEKK1: Dual Function as a Protein Kinase and a Ubiquitin Protein Ligase

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