Abstract
Protein kinase C (PKC)-activating phorbol esters protect T cells from Fas-induced apoptosis. However, the mechanism of this protective effect and the identity of the relevant PKC isoform(s) are poorly understood. Here, we show that PKCtheta plays a selective and important role in this protection. Fas triggering led to a selective caspase-3-dependent cleavage of the enzyme and proteasome-mediated degradation and inactivation of its catalytic fragment. These events preceded the onset of apoptosis. Pharmacological inhibition of PKCtheta promoted Fas-mediated apoptosis in three different types of T cells. Conversely, constitutively active PKCtheta (and, to a lesser degree, PKCepsilon) selectively protected T cells from Fas-induced apoptosis. We provide evidence that the distant Bcl-2 family member, BAD, is a PKCtheta substrate, is phosphorylated by TCR stimulation, and can mediate at least in part the anti-apoptotic effect of PKCtheta.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis / immunology
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Carrier Proteins / metabolism*
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Carrier Proteins / physiology
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Cell Survival / immunology
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Enzyme Activation / immunology
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Fas Ligand Protein
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Humans
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Hybridomas
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Hydrolysis
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Isoenzymes / metabolism
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Isoenzymes / physiology*
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Jurkat Cells
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Ligands
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Membrane Glycoproteins / immunology
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Membrane Glycoproteins / metabolism
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NF-kappa B / physiology
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Phosphorylation
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Protein Kinase C / metabolism
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Protein Kinase C / physiology*
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Protein Kinase C-theta
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Signal Transduction / immunology*
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Substrate Specificity / immunology
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T-Lymphocytes / cytology*
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T-Lymphocytes / enzymology*
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T-Lymphocytes / metabolism
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bcl-Associated Death Protein
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fas Receptor / metabolism
Substances
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BAD protein, human
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Carrier Proteins
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FASLG protein, human
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Fas Ligand Protein
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Isoenzymes
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Ligands
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Membrane Glycoproteins
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NF-kappa B
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bcl-Associated Death Protein
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fas Receptor
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PRKCQ protein, human
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Protein Kinase C
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Protein Kinase C-theta