Caspase-mediated calcineurin activation contributes to IL-2 release during T cell activation.
Calcineurin, a Ca(2+)/calmodulin-dependent Ser/Thr phosphatase (protein phosphatase 2B), plays a critical role in IL-2 production during T cell activation. It has been previously reported that IL-2 release in activated Jurkat T requires caspase-like activity (Posmantur et al. (1998) Exp. Cell. Res. 244, 302-309). We report here that the 60-kDa catalytic subunit of calcineurin A (Cn A) was partially cleaved to a 45-kDa form in phytohemagglutinin A (PHA) or phorbol ester + ionomycin (P + I)-activated Jurkat cells. In parallel, proteolytic activation of upstream caspases (caspase-8 and -9) as well as effector caspase-3 was also observed. Cn A cleavage was caspase mediated, since it was inhibitable by pan-caspase inhibitor Cbz-Asp-CH(2)OC(O)-2,6-dichlorobenzene (Z-D-DCB). Cn A cleavage was also observed when purified calcineurin was digested in vitro with caspase-3. Truncated Cn A was associated with enhanced phosphatase activity and reduced calmodulin sensitivity. Furthermore, in PHA or P + I-activated Jurkat cells, dephosphorylation of calcineurin substrate NFATc (a transcription factor known to be involved in transactivation of the IL-2 gene), was also suppressed by Z-D-DCB. Taken together, our results suggest that caspase-mediated cleavage of Cn A contributes to IL-2 production during T cell activation.
Mukerjee
N
N
Laboratory of Neuro-biochemistry, Department of CNS Molecular Sciences, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
McGinnis
K M
KM
Gnegy
M E
ME
Wang
K K
KK
D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010766:Phosphorylation / Q000187:drug effects; D010835:Phytohemagglutinins / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D013049:Spectrin / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein
D065095:Calcineurin Inhibitors; D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D007476:Ionophores; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010835:Phytohemagglutinins; D011506:Proteins; D014157:Transcription Factors; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C093260:benzyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene; D013049:Spectrin; D001224:Aspartic Acid; D015759:Ionomycin; D016572:Cyclosporine; D019703:Calcineurin; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate