Protein kinase C-theta mediates a selective T cell survival signal via phosphorylation of BAD
M Villalba1, P Bushway, A Altman
1Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA. villalba@liai.org
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.
Insights
Protein kinase C-theta (PKCtheta) protects T cells from Fas-induced apoptosis by preventing enzyme degradation. This finding reveals a key mechanism for T cell survival.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Protein kinase C (PKC) activators protect T cells from Fas-induced apoptosis.
- The specific PKC isoforms and mechanisms involved remain unclear.
Purpose of the Study:
- To elucidate the role of PKC isoforms in T cell protection against Fas-mediated apoptosis.
- To identify the molecular mechanisms underlying this protective effect.
Main Methods:
- Investigated the role of PKCtheta using pharmacological inhibitors and constitutively active forms.
- Analyzed caspase-3 cleavage, proteasomal degradation, and BAD phosphorylation.
- Utilized three different T cell types for experiments.
Main Results:
- PKCtheta selectively protects T cells from Fas-induced apoptosis.
- Fas triggering causes caspase-3-dependent cleavage and proteasomal degradation of PKCtheta.
- Constitutively active PKCtheta and PKCepsilon conferred protection; PKCtheta inhibition promoted apoptosis.
- BAD, a Bcl-2 family member, is a PKCtheta substrate phosphorylated by TCR stimulation, mediating anti-apoptotic effects.
Conclusions:
- PKCtheta plays a critical role in preventing Fas-induced T cell apoptosis.
- PKCtheta degradation is a key event preceding apoptosis.
- Phosphorylation of BAD by PKCtheta contributes to T cell survival.
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