Regulation of monocyte apoptosis by the protein kinase Cδ-dependent phosphorylation of caspase-3

Abstract

Monocytes are central components of the innate immune response and normally circulate for a short period of time before undergoing spontaneous apoptosis. During inflammation, differentiation, or oncogenic transformation, the life span of monocytes is prolonged by preventing the activation of the apoptotic program. Here we showed that caspase-3, a cysteine protease required for monocyte apoptosis, is a phosphoprotein. We identified protein kinase Cδ (PKCδ) as a member of the protein kinase C family that associates with and phosphorylates caspase-3. The PKCδ-dependent phosphorylation of caspase-3 resulted in an increase in the activity of caspase-3. This effect of PKCδ is specific to caspase-3, as evidenced by the absence of similar effects on caspase-9. The activity of PKCδ precedes the activation of caspase-3 during spontaneous monocyte apoptosis and in monocyte-induced apoptosis. We found that the overexpression of PKCδ resulted in an increase of apoptosis, whereas its inhibition blocked caspase-3 activity and decreased apoptosis. Our results provided evidence that the PKCδ-dependent phosphorylation of caspase-3 provided a novel pro-apoptotic mechanism involved in the regulation of monocyte life span. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.