Regulation of monocyte apoptosis by the protein kinase Cdelta-dependent phosphorylation of caspase-3.
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 Cdelta (PKCdelta) as a member of the protein kinase C family that associates with and phosphorylates caspase-3. The PKCdelta-dependent phosphorylation of caspase-3 resulted in an increase in the activity of caspase-3. This effect of PKCdelta is specific to caspase-3, as evidenced by the absence of similar effects on caspase-9. The activity of PKCdelta precedes the activation of caspase-3 during spontaneous monocyte apoptosis and in monocyte-induced apoptosis. We found that the overexpression of PKCdelta resulted in an increase of apoptosis, whereas its inhibition blocked caspase-3 activity and decreased apoptosis. Our results provided evidence that the PKCdelta-dependent phosphorylation of caspase-3 provided a novel pro-apoptotic mechanism involved in the regulation of monocyte life span.
Voss
Oliver H
OH
Heart and Lung Research Institute and Division of Pulmonary and Critical Care, Department of Molecular Genetics, the Ohio State University, Columbus, Ohio 43210, USA.
Kim
Sunghan
S
Wewers
Mark D
MD
Doseff
Andrea I
AI
D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D020868:Gene Silencing; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry; D010766:Phosphorylation; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D013997:Time Factors; D014162:Transfection
D004791:Enzyme Inhibitors; D010750:Phosphoproteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases