T-cell death following immune activation is mediated by mitochondria-localized SARM

• Published in: Cell death and differentiation 2013-03, Vol.20 (3), p.478-489
• Main Authors: Panneerselvam, P, Singh, L P, Selvarajan, V, Chng, W J, Ng, S B, Tan, N S, Ho, B, Chen, J, Ding, J L
• Format: Article
• Language: English
• Subjects: 631/250/1619/554; 631/80/82/23; 692/699/67/1990/291; adaptor proteins; Animals; Apoptosis; Armadillo Domain Proteins - antagonists & inhibitors; Armadillo Domain Proteins - genetics; Armadillo Domain Proteins - metabolism; Autoimmune diseases; Bcl-2 protein; bcl-2-Associated X Protein - antagonists & inhibitors; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Bcl-x protein; bcl-X Protein - antagonists & inhibitors; bcl-X Protein - genetics; bcl-X Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Caspase 9 - metabolism; Cell activation; Cell Biology; Cell Cycle Analysis; Cell death; Cell proliferation; Cell survival; Cells, Cultured; Cytoskeletal Proteins - antagonists & inhibitors; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Cytotoxicity; Depolarization; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Heat; HEK293 Cells; Homeostasis; Humans; Infection; Influenza; Interleukin 1; Life Sciences; Lymphocyte Activation; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma, T-Cell - metabolism; Lymphoma, T-Cell - pathology; Mice; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; Original Paper; Phosphorylation; Proto-Oncogene Proteins c-bcl-2 - metabolism; Reactive oxygen species; Receptor mechanisms; RNA Interference; RNA, Small Interfering - metabolism; Stem Cells; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Toll-like receptors; Transfection; X protein
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2012.144

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.