Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/99779
Title: T-cell death following immune activation is mediated by mitochondria-localized SARM
Authors: Ho, B.
Chen, J.
Singh, L. P.
Selvarajan, V.
Ng, S. B.
Tan, N. S.
Panneerselvam, P.
Chng, Wee Joo
Ding, Jeak Ling
Keywords: DRNTU::Science::Biological sciences
Issue Date: 2013
Source: Panneerselvam, P., Singh, L. P., Selvarajan, V., Chng, W. J., Ng, S. B., Tan, N. S., et al. (2013). T-cell death following immune activation is mediated by mitochondria-localized SARM. Cell death and differentiation, 20, 478-489.
Series/Report no.: Cell death and differentiation
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.
URI: https://hdl.handle.net/10356/99779
http://hdl.handle.net/10220/17575
DOI: 10.1038/cdd.2012.144
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:SBS Journal Articles

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