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...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) Vol. 195; no. 12; pp. 5780 - 5786
Main Authors: Dasgupta, Asish, Chen, Kuang-Hueih, Munk, Rachel B, Sasaki, Carl Y, Curtis, Jessica, Longo, Dan L, Ghosh, Paritosh
Format: Journal Article
Language:English
Published: England 15.12.2015
Subjects:
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
ISSN:1550-6606
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1550-6606
DOI:10.4049/jimmunol.1501023