title: T-cell death following immune activation is mediated by mitochondria-localized SARM.
abstract: 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.
authors.affiliation: Computation and Systems Biology, Singapore-MIT Alliance, Singapore.
authors.forename: P
authors.initials: P
authors.lastname: Panneerselvam
authors.forename: L P
authors.initials: LP
authors.lastname: Singh
authors.forename: V
authors.initials: V
authors.lastname: Selvarajan
authors.forename: W J
authors.initials: WJ
authors.lastname: Chng
authors.forename: S B
authors.initials: SB
authors.lastname: Ng
authors.forename: N S
authors.initials: NS
authors.lastname: Tan
authors.forename: B
authors.initials: B
authors.lastname: Ho
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: J L
authors.initials: JL
authors.lastname: Ding
mesh_terms: D000818:Animals; D017209:Apoptosis; D051186:Armadillo Domain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008213:Lymphocyte Activation; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D051186:Armadillo Domain Proteins; D003598:Cytoskeletal Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C435689:SARM1 protein, human; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D053453:Caspase 9