CD95 (Fas)-induced caspase-mediated proteolysis of NF-kappaB.
Activation of the nuclear factor (NF)-kappaB transcription factor is instrumental for the immune response and the survival of peripheral activated T cells. We demonstrate that ligation of CD95 (Fas/APO1), a potent apoptotic stimulus in lymphocytes, results in repression of NF-kappaB activity in Jurkat T cells by inducing the proteolytic cleavage of NF-kappaB p65 (Rel A) and p50. Inhibition of caspase-3-related proteases by a specific acetylated aldehyde (Ac-DEVD-CHO) prevented CD95-induced cleavage of p65 (RelA) or p50 and restored the inducibility of NF-kappaB in cells treated with an antibody against CD95. The addition of recombinant caspase-3 also resulted in proteolytic cleavage of RelA p65 and p50 in vitro. TNF-alpha treatment, unlike CD95 ligation, did not result in the death of Jurkat cells but did so in the presence of I kappaB alphaM, a transdominant inhibitor of NF-kappaB. These results suggest that intact, functional NF-kappaB maintains the survival of activated T cells, and that CD95-induced cleavage of NF-kappaB subunits sensitizes T cells to apoptosis and, hence, facilitates the decay of an immune response.
Ravi
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Johns Hopkins Oncology Center, Division of Experimental Therapeutics and Pharmacology, Baltimore, Maryland 21287, USA.
Bedi
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Fuchs
E J
EJ
Bedi
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D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction; D019014:fas Receptor / Q000502:physiology*
D016328:NF-kappa B; D019014:fas Receptor; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases