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Protein Kinase D Orchestrates the Activation of DRAK2 in Response to TCR-Induced Ca2+ Influx and Mitochondrial Reactive Oxygen Generation
- Source :
- The Journal of Immunology. 186:940-950
- Publication Year :
- 2011
- Publisher :
- The American Association of Immunologists, 2011.
-
Abstract
- DRAK2 is a serine/threonine kinase highly enriched in lymphocytes that raises the threshold for T cell activation and maintains T cell survival following productive activation. T cells lacking DRAK2 are prone to activation under suboptimal conditions and exhibit enhanced calcium responses to AgR stimulation. Despite this, mice lacking DRAK2 are resistant to organ-specific autoimmune diseases due to defective autoreactive T cell survival. DRAK2 kinase activity is induced by AgR signaling, and in this study we show that the induction of DRAK2 activity requires Ca2+ influx through the Ca2+ release-activated Ca2+ channel formed from Orai1 subunits. Blockade of DRAK2 activity with the protein kinase D (PKD) inhibitor Gö6976 or expression of a kinase-dead PKD mutant prevented activation of DRAK2, whereas a constitutively active PKD mutant promoted DRAK2 function. Knockdown of PKD in T cells strongly blocked endogenous DRAK2 activation following TCR ligation, implicating PKD as an essential intermediate in the activation of DRAK2 by Ca2+ influx. Furthermore, we identify DRAK2 as a novel substrate of PKD, and demonstrate that DRAK2 and PKD physically interact under conditions that activate PKD. Mitochondrial generation of reactive oxygen intermediates was necessary and sufficient for DRAK2 activation in response to Ca2+ influx. Taken together, DRAK2 and PKD form a novel signaling module that controls calcium homeostasis following T cell activation.
- Subjects :
- T-Lymphocytes
T cell
Immunology
Receptors, Antigen, T-Cell
Mice, Transgenic
Protein Serine-Threonine Kinases
Biology
Lymphocyte Activation
Jurkat cells
Article
Jurkat Cells
Mice
medicine
Animals
Homeostasis
Humans
Immunology and Allergy
Calcium Signaling
Kinase activity
Protein Kinase C
Protein kinase C
Calcium signaling
Mice, Knockout
Kinase
ORAI1
T-cell receptor
musculoskeletal system
Clone Cells
Mitochondria
Cell biology
Enzyme Activation
Mice, Inbred C57BL
medicine.anatomical_structure
cardiovascular system
Apoptosis Regulatory Proteins
Reactive Oxygen Species
Subjects
Details
- ISSN :
- 15506606 and 00221767
- Volume :
- 186
- Database :
- OpenAIRE
- Journal :
- The Journal of Immunology
- Accession number :
- edsair.doi.dedup.....d23b02c6d681ca17e3ae0d5203c852f3