P2X7 receptor-dependent and -independent T cell death is induced by nicotinamide adenine dinucleotide.
Adding NAD to murine T lymphocytes inhibits their functions and induces annexin V binding. This report shows that NAD induces cell death in a subset of T cells within seconds whereas others do not die until many hours later. Low NAD concentrations (<10 microM) suffice to trigger rapid cell death, which is associated with annexin V binding and membrane pore formation, is not blocked by the caspase inhibitor Z-VADfmk, and requires functional P2X7 receptors. The slower induction of death requires higher NAD concentrations (>100 microM), is blocked by caspase inhibitor Z-VADfmk, is associated with DNA fragmentation, and does not require P2X7 receptors. T cells degrade NAD to ADP-ribose (ADPR), and adding ADPR to T cells leads to slow but not rapid cell death. NAD but not ADPR provides the substrate for ADP-ribosyltransferase (ART-2)-mediated attachment of ADP-ribosyl groups to cell surface proteins; expression of ART-2 is required for NAD to trigger rapid but not slow cell death. These results support the hypothesis that cell surface ART-2 uses NAD but not ADPR to attach ADP-ribosyl groups to the cell surface, and that these groups act as ligands for P2X7 receptors that then induce rapid cell death. Adding either NAD or ADPR also triggers a different set of mechanisms, not requiring ART-2 or P2X7 receptors that more slowly induce cell death.
Kawamura
Hiroki
H
Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
Aswad
Fred
F
Minagawa
Masahiro
M
Malone
Karen
K
Kaslow
Harvey
H
Koch-Nolte
Friederich
F
Schott
William H
WH
Leiter
Edward H
EH
Dennert
Gunther
G
D036002:ADP Ribose Transferases / Q000502:physiology; D000246:Adenosine Diphosphate Ribose / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009243:NAD / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D013997:Time Factors
D006131:Growth Inhibitors; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D009243:NAD; D000246:Adenosine Diphosphate Ribose; C011038:nicotinamide 1,N(6)-ethenoadenine dinucleotide; D036002:ADP Ribose Transferases