Protein kinase C-theta mediates a selective T cell survival signal via phosphorylation of BAD.
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.
Villalba
M
M
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA. villalba@liai.org
Bushway
P
P
Altman
A
A
D017209:Apoptosis / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D002470:Cell Survival / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D053222:Fas Ligand Protein; D006801:Humans; D006825:Hybridomas; D006868:Hydrolysis; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology*; D019169:Jurkat Cells; D008024:Ligands; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D000074121:Protein Kinase C-theta; D015398:Signal Transduction / Q000276:immunology*; D013379:Substrate Specificity / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D051025:bcl-Associated Death Protein; D019014:fas Receptor / Q000378:metabolism
C494819:BAD protein, human; D002352:Carrier Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007527:Isoenzymes; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D051025:bcl-Associated Death Protein; D019014:fas Receptor; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta