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Novel Role for Mitochondria: Protein Kinase Cθ-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death
- Source :
- Molecular and Cellular Biology. 27:3625-3639
- Publication Year :
- 2007
- Publisher :
- Informa UK Limited, 2007.
-
Abstract
- Reactive oxygen species (ROS) play a key role in regulation of activation-induced T-cell death (AICD) by induction of CD95L expression. However, the molecular source and the signaling steps necessary for ROS production are largely unknown. Here, we show that the proximal T-cell receptor-signaling machinery, including ZAP70 (zeta chain-associated protein kinase 70), LAT (linker of activated T cells), SLP76 (SH2 domain-containing leukocyte protein of 76 kDa), PLCgamma1 (phospholipase Cgamma1), and PKCtheta (protein kinase Ctheta), are crucial for ROS production. PKCtheta is translocated to the mitochondria. By using cells depleted of mitochondrial DNA, we identified the mitochondria as the source of activation-induced ROS. Inhibition of mitochondrial electron transport complex I assembly by small interfering RNA (siRNA)-mediated knockdown of the chaperone NDUFAF1 resulted in a block of ROS production. Complex I-derived ROS are converted into a hydrogen peroxide signal by the mitochondrial superoxide dismutase. This signal is essential for CD95L expression, as inhibition of complex I assembly by NDUFAF1-specific siRNA prevents AICD. Similar results were obtained when metformin, an antidiabetic drug and mild complex I inhibitor, was used. Thus, we demonstrate for the first time that PKCtheta-dependent ROS generation by mitochondrial complex I is essential for AICD.
- Subjects :
- Small interfering RNA
Fas Ligand Protein
T-Lymphocytes
Receptors, Antigen, T-Cell
Biology
Mitochondrion
Lymphocyte Activation
Jurkat Cells
Humans
Hypoglycemic Agents
RNA, Small Interfering
Protein kinase A
Molecular Biology
Protein Kinase C
Protein kinase C
chemistry.chemical_classification
Reactive oxygen species
Electron Transport Complex I
Cell Death
ZAP70
NADH Dehydrogenase
Articles
Cell Biology
Metformin
Mitochondria
Cell biology
Isoenzymes
Oxidative Stress
chemistry
Biochemistry
Protein Kinase C-theta
Chaperone (protein)
biology.protein
Signal transduction
Reactive Oxygen Species
Signal Transduction
Subjects
Details
- ISSN :
- 10985549
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- Molecular and Cellular Biology
- Accession number :
- edsair.doi.dedup.....ca7014afcc00a988fca918792f52f3b4
- Full Text :
- https://doi.org/10.1128/mcb.02295-06