Downregulation of miR-200a-3p, targeting CtBP2 complex, is involved in the hypoproduction of IL-2 in systemic lupus erythematosus-derived T cells

Eri Katsuyama, Minglu Yan, Katsue Sunahori Watanabe, Syun Matsushima, Yuriko Yamamura, Sumie Hiramatsu, Keiji Ohashi, Haruki Watanabe, Takayuki Katsuyama, Sonia Zeggar, Nobuya Yoshida, Vaishali R. Moulton, George C. Tsokos, Kenei Sada, Jun Wada

Research output: Contribution to journalArticle

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Abstract

Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. In this study, we report that decreased microRNA (miR)-200a-3p causes IL-2 hypoproduction through zinc finger E-box binding homeobox (ZEB)1 and C-terminal binding protein 2 (CtBP2) in a lupus-prone mouse. First, we performed RNA sequencing to identify candidate microRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, whereas its putative targets, ZEB2 and CtBP2, were upregulated in CD4+T cells from MRL/lpr-Tnfrsf6lpr mice compared with C57BL/6J mice. ZEB1 and ZEB2 comprise the ZEB family and suppress various genes, including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance, and insufficient IL-2 production upon stimulation has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p causes IL-2 deficit through the ZEB1-CtBP2 and/or ZEB2-CtBP2 complex in SLE CD4+T cells. Overexpression of miR-200a-3p induced IL-2 production by downregulating ZEB1, ZEB2, and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promotes IL-2 expression by reducing the binding of suppressive ZEB1-CtBP2 and ZEB2-CtBP2 complexes on negative regulatory element A in the IL-2 promoter in EL4 cells. Interestingly, the ZEB1-CtBP2 complex on negative regulatory element Awas significantly upregulated after PMA/ionomycin stimulation in lupus CD4+T cells. Our studies have revealed a new epigenetic pathway in the control of IL-2 production in SLE whereby low levels of miR-200a-3p accumulate the binding of the ZEB1-CtBP2 complex to the IL-2 promoter and suppress IL-2 production.

Original languageEnglish
Pages (from-to)4268-4276
Number of pages9
JournalJournal of Immunology
Volume198
Issue number11
DOIs
Publication statusPublished - Jun 1 2017

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MicroRNAs
Systemic Lupus Erythematosus
Interleukin-2
Down-Regulation
T-Lymphocytes
C-terminal binding protein
Inbred MRL lpr Mouse
RNA Sequence Analysis
Immune Tolerance
Ionomycin
Inbred C57BL Mouse
Epigenomics
Autoantibodies
Cell Line
Messenger RNA

ASJC Scopus subject areas

  • Immunology

Cite this

Downregulation of miR-200a-3p, targeting CtBP2 complex, is involved in the hypoproduction of IL-2 in systemic lupus erythematosus-derived T cells. / Katsuyama, Eri; Yan, Minglu; Watanabe, Katsue Sunahori; Matsushima, Syun; Yamamura, Yuriko; Hiramatsu, Sumie; Ohashi, Keiji; Watanabe, Haruki; Katsuyama, Takayuki; Zeggar, Sonia; Yoshida, Nobuya; Moulton, Vaishali R.; Tsokos, George C.; Sada, Kenei; Wada, Jun.

In: Journal of Immunology, Vol. 198, No. 11, 01.06.2017, p. 4268-4276.

Research output: Contribution to journalArticle

Katsuyama, E, Yan, M, Watanabe, KS, Matsushima, S, Yamamura, Y, Hiramatsu, S, Ohashi, K, Watanabe, H, Katsuyama, T, Zeggar, S, Yoshida, N, Moulton, VR, Tsokos, GC, Sada, K & Wada, J 2017, 'Downregulation of miR-200a-3p, targeting CtBP2 complex, is involved in the hypoproduction of IL-2 in systemic lupus erythematosus-derived T cells', Journal of Immunology, vol. 198, no. 11, pp. 4268-4276. https://doi.org/10.4049/jimmunol.1601705
Katsuyama, Eri ; Yan, Minglu ; Watanabe, Katsue Sunahori ; Matsushima, Syun ; Yamamura, Yuriko ; Hiramatsu, Sumie ; Ohashi, Keiji ; Watanabe, Haruki ; Katsuyama, Takayuki ; Zeggar, Sonia ; Yoshida, Nobuya ; Moulton, Vaishali R. ; Tsokos, George C. ; Sada, Kenei ; Wada, Jun. / Downregulation of miR-200a-3p, targeting CtBP2 complex, is involved in the hypoproduction of IL-2 in systemic lupus erythematosus-derived T cells. In: Journal of Immunology. 2017 ; Vol. 198, No. 11. pp. 4268-4276.
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abstract = "Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. In this study, we report that decreased microRNA (miR)-200a-3p causes IL-2 hypoproduction through zinc finger E-box binding homeobox (ZEB)1 and C-terminal binding protein 2 (CtBP2) in a lupus-prone mouse. First, we performed RNA sequencing to identify candidate microRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, whereas its putative targets, ZEB2 and CtBP2, were upregulated in CD4+T cells from MRL/lpr-Tnfrsf6lpr mice compared with C57BL/6J mice. ZEB1 and ZEB2 comprise the ZEB family and suppress various genes, including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance, and insufficient IL-2 production upon stimulation has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p causes IL-2 deficit through the ZEB1-CtBP2 and/or ZEB2-CtBP2 complex in SLE CD4+T cells. Overexpression of miR-200a-3p induced IL-2 production by downregulating ZEB1, ZEB2, and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promotes IL-2 expression by reducing the binding of suppressive ZEB1-CtBP2 and ZEB2-CtBP2 complexes on negative regulatory element A in the IL-2 promoter in EL4 cells. Interestingly, the ZEB1-CtBP2 complex on negative regulatory element Awas significantly upregulated after PMA/ionomycin stimulation in lupus CD4+T cells. Our studies have revealed a new epigenetic pathway in the control of IL-2 production in SLE whereby low levels of miR-200a-3p accumulate the binding of the ZEB1-CtBP2 complex to the IL-2 promoter and suppress IL-2 production.",
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AU - Yan, Minglu

AU - Watanabe, Katsue Sunahori

AU - Matsushima, Syun

AU - Yamamura, Yuriko

AU - Hiramatsu, Sumie

AU - Ohashi, Keiji

AU - Watanabe, Haruki

AU - Katsuyama, Takayuki

AU - Zeggar, Sonia

AU - Yoshida, Nobuya

AU - Moulton, Vaishali R.

AU - Tsokos, George C.

AU - Sada, Kenei

AU - Wada, Jun

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N2 - Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. In this study, we report that decreased microRNA (miR)-200a-3p causes IL-2 hypoproduction through zinc finger E-box binding homeobox (ZEB)1 and C-terminal binding protein 2 (CtBP2) in a lupus-prone mouse. First, we performed RNA sequencing to identify candidate microRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, whereas its putative targets, ZEB2 and CtBP2, were upregulated in CD4+T cells from MRL/lpr-Tnfrsf6lpr mice compared with C57BL/6J mice. ZEB1 and ZEB2 comprise the ZEB family and suppress various genes, including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance, and insufficient IL-2 production upon stimulation has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p causes IL-2 deficit through the ZEB1-CtBP2 and/or ZEB2-CtBP2 complex in SLE CD4+T cells. Overexpression of miR-200a-3p induced IL-2 production by downregulating ZEB1, ZEB2, and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promotes IL-2 expression by reducing the binding of suppressive ZEB1-CtBP2 and ZEB2-CtBP2 complexes on negative regulatory element A in the IL-2 promoter in EL4 cells. Interestingly, the ZEB1-CtBP2 complex on negative regulatory element Awas significantly upregulated after PMA/ionomycin stimulation in lupus CD4+T cells. Our studies have revealed a new epigenetic pathway in the control of IL-2 production in SLE whereby low levels of miR-200a-3p accumulate the binding of the ZEB1-CtBP2 complex to the IL-2 promoter and suppress IL-2 production.

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