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T-cell death following immune activation is mediated by mitochondria-localized SARM
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T-cell death following immune activation is mediated by mitochondria-localized SARM
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T-cell death following immune activation is mediated by mitochondria-localized SARM
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Journal Article
T-cell death following immune activation is mediated by mitochondria-localized SARM
2013
Overview
Following acute-phase infection, activated T cells are terminated to achieve immune homeostasis, failure of which results in lymphoproliferative and autoimmune diseases. We report that sterile
α
- and heat armadillo-motif-containing protein (SARM), the most conserved Toll-like receptors adaptor, is proapoptotic during T-cell immune response. SARM expression is significantly reduced in natural killer (NK)/T lymphoma patients compared with healthy individuals, suggesting that decreased SARM supports NK/T-cell proliferation. T cells knocked down of SARM survived and proliferated more significantly compared with wild-type T cells following influenza infection
in vivo
. During activation of cytotoxic T cells, the SARM level fell before rising, correlating inversely with cell proliferation and subsequent T-cell clearance. SARM knockdown rescued T cells from both activation- and neglect-induced cell deaths. The mitochondria-localized SARM triggers intrinsic apoptosis by generating reactive oxygen species and depolarizing the mitochondrial potential. The proapoptotic function is attributable to the C-terminal sterile alpha motif and Toll/interleukin-1 receptor domains. Mechanistically, SARM mediates intrinsic apoptosis via B cell lymphoma-2 (Bcl-2) family members. SARM suppresses B cell lymphoma-extra large (Bcl-xL) and downregulates extracellular signal-regulated kinase phosphorylation, which are cell survival effectors. Overexpression of Bcl-xL and double knockout of Bcl-2 associated X protein and Bcl-2 homologous antagonist killer substantially reduced SARM-induced apoptosis. Collectively, we have shown how T-cell death following infection is mediated by SARM-induced intrinsic apoptosis, which is crucial for T-cell homeostasis.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Animals
/ Armadillo Domain Proteins - antagonists & inhibitors
/ Armadillo Domain Proteins - genetics
/ Armadillo Domain Proteins - metabolism
/ bcl-2-Associated X Protein - antagonists & inhibitors
/ bcl-2-Associated X Protein - genetics
/ bcl-2-Associated X Protein - metabolism
/ bcl-X Protein - antagonists & inhibitors
/ Biomedical and Life Sciences
/ Cytoskeletal Proteins - antagonists & inhibitors
/ Cytoskeletal Proteins - genetics
/ Cytoskeletal Proteins - metabolism
/ Extracellular signal-regulated kinase
/ Extracellular Signal-Regulated MAP Kinases - metabolism
/ Heat
/ Humans
/ Lymphoma
/ Lymphoma, T-Cell - metabolism
/ Lymphoma, T-Cell - pathology
/ Mice
/ Proto-Oncogene Proteins c-bcl-2 - metabolism
