ADP-ribosylation of rho by C3 ribosyltransferase inhibits IL-2 production and sustained calcium influx in activated T cells.
Activation of the T lymphocyte induces dramatic cytoskeletal changes, and there is increasing evidence that disruption of the cytoskeleton inhibits early and late events of T cell signal transduction. However, relatively little is known about the signaling molecules involved in activation-induced cytoskeletal rearrangement. The rho family of small GTP-binding proteins, which include rho, rac, and cdc42, regulates the cytoskeleton and coordinates various cellular functions via their many effector targets. In prior studies, the Clostridium botulinum toxin C3 exoenzyme has been used to ADP-ribosylate and inactivate rho. In this study, we demonstrate that treatment of T cells with C3 exoenzyme inhibits IL-2 transcription following ligation of the TCR. Inhibition of IL-2 expression correlated with loss of sustained increase in [Ca+2]i and mitogen activated protein kinase (MAPK/Erk) activity, but not with activation of the tyrosine kinase, lck. These findings are the first to show that ADP-ribosylation of rho by C3 ribosyltransferase (exoenzyme) inhibits IL-2 production due, in part, to the requirement for sustained calcium influx and MAPK activation after Ag receptor ligation.
Angkachatchai
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Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Finkel
T H
TH
D036002:ADP Ribose Transferases / Q000378:metabolism*; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D001905:Botulinum Toxins; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020013:Calcium Signaling / Q000276:immunology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D003014:Clostridium botulinum / Q000201:enzymology; D004789:Enzyme Activation / Q000276:immunology; D004790:Enzyme Induction / Q000276:immunology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D007376:Interleukin-2; D000246:Adenosine Diphosphate Ribose; D014443:Tyrosine; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D001905:Botulinum Toxins; D019204:GTP-Binding Proteins; D002118:Calcium