Mechanism of Activation-Induced Downregulation of Mitofusin 2 in Human Peripheral Blood T Cells
Mitofusin 2 (Mfn2), a mitochondrial protein, was shown to have antiproliferative properties when overexpressed. In this article, we show that activation of resting human peripheral blood T cells caused downregulation of Mfn2 levels. This downregulation of Mfn2 was blocked by different inhibitors (mT...
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| Vydáno v: | The Journal of immunology (1950) Ročník 195; číslo 12; s. 5780 - 5786 |
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| Hlavní autoři: | , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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England
15.12.2015
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| ISSN: | 1550-6606 |
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| Abstract | Mitofusin 2 (Mfn2), a mitochondrial protein, was shown to have antiproliferative properties when overexpressed. In this article, we show that activation of resting human peripheral blood T cells caused downregulation of Mfn2 levels. This downregulation of Mfn2 was blocked by different inhibitors (mTOR inhibitor rapamycin, PI3K inhibitor LY294002, and Akt inhibitor A443654), producing cells that were arrested in the G0/G1 stage of the cell cycle. Furthermore, the activation-induced downregulation of Mfn2 preceded the entry of the cells into the cell cycle, suggesting that Mfn2 downregulation is a prerequisite for activated T cell entry into the cell cycle. Accordingly, small interfering RNA-mediated knockdown of Mfn2 resulted in increased T cell proliferation. Overexpression of constitutively active AKT resulted in the downregulation of Mfn2, which can be blocked by a proteasome inhibitor. Akt-mediated downregulation of Mfn2 was via the mTORC1 pathway because this downregulation was blocked by rapamycin, and overexpression of wild-type, but not kinase-dead mTOR, caused Mfn2 downregulation. Our data suggested that activation-induced reactive oxygen species production plays an important role in the downregulation of Mfn2. Collectively, our data suggest that the PI3K-AKT-mTOR pathway plays an important role in activation-induced downregulation of Mfn2 and subsequent proliferation of resting human T cells. |
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| AbstractList | Mitofusin 2 (Mfn2), a mitochondrial protein, was shown to have antiproliferative properties when overexpressed. In this article, we show that activation of resting human peripheral blood T cells caused downregulation of Mfn2 levels. This downregulation of Mfn2 was blocked by different inhibitors (mTOR inhibitor rapamycin, PI3K inhibitor LY294002, and Akt inhibitor A443654), producing cells that were arrested in the G0/G1 stage of the cell cycle. Furthermore, the activation-induced downregulation of Mfn2 preceded the entry of the cells into the cell cycle, suggesting that Mfn2 downregulation is a prerequisite for activated T cell entry into the cell cycle. Accordingly, small interfering RNA-mediated knockdown of Mfn2 resulted in increased T cell proliferation. Overexpression of constitutively active AKT resulted in the downregulation of Mfn2, which can be blocked by a proteasome inhibitor. Akt-mediated downregulation of Mfn2 was via the mTORC1 pathway because this downregulation was blocked by rapamycin, and overexpression of wild-type, but not kinase-dead mTOR, caused Mfn2 downregulation. Our data suggested that activation-induced reactive oxygen species production plays an important role in the downregulation of Mfn2. Collectively, our data suggest that the PI3K-AKT-mTOR pathway plays an important role in activation-induced downregulation of Mfn2 and subsequent proliferation of resting human T cells. |
| Author | Chen, Kuang-Hueih Munk, Rachel B Dasgupta, Asish Ghosh, Paritosh Curtis, Jessica Sasaki, Carl Y Longo, Dan L |
| Author_xml | – sequence: 1 givenname: Asish surname: Dasgupta fullname: Dasgupta, Asish organization: Lymphocyte Cell Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD; and – sequence: 2 givenname: Kuang-Hueih surname: Chen fullname: Chen, Kuang-Hueih organization: Lymphocyte Cell Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD; and – sequence: 3 givenname: Rachel B surname: Munk fullname: Munk, Rachel B organization: Lymphocyte Cell Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD; and – sequence: 4 givenname: Carl Y surname: Sasaki fullname: Sasaki, Carl Y organization: Lymphocyte Cell Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD; and – sequence: 5 givenname: Jessica surname: Curtis fullname: Curtis, Jessica organization: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224 – sequence: 6 givenname: Dan L surname: Longo fullname: Longo, Dan L organization: Lymphocyte Cell Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD; and – sequence: 7 givenname: Paritosh surname: Ghosh fullname: Ghosh, Paritosh email: ghoshp@grc.nia.nih.gov organization: Lymphocyte Cell Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD; and ghoshp@grc.nia.nih.gov |
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| Snippet | Mitofusin 2 (Mfn2), a mitochondrial protein, was shown to have antiproliferative properties when overexpressed. In this article, we show that activation of... |
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| SubjectTerms | Cell Cycle - genetics Cell Line, Tumor Cell Proliferation - genetics Chromones - pharmacology Down-Regulation - drug effects Down-Regulation - genetics GTP Phosphohydrolases - genetics GTP Phosphohydrolases - metabolism Humans Indazoles - pharmacology Indoles - pharmacology Leukocytes, Mononuclear - immunology Lymphocyte Activation Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism Morpholines - pharmacology Phosphatidylinositol 3-Kinases - metabolism Proto-Oncogene Proteins c-akt - metabolism Reactive Oxygen Species - metabolism RNA, Small Interfering - genetics Signal Transduction - genetics Sirolimus - pharmacology T-Lymphocytes - drug effects T-Lymphocytes - physiology TOR Serine-Threonine Kinases - metabolism |
| Title | Mechanism of Activation-Induced Downregulation of Mitofusin 2 in Human Peripheral Blood T Cells |
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