CD95 (Fas)-induced caspase-mediated proteolysis of NF-κB

Activation of the nuclear factor (NF)-κB 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-κB activity in Jurkat T cells by inducing the proteolytic cleavage of NF-κB p65 (RelA) 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-κB 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-α treatment, unlike CD95 ligation, did not result in the death of Jurkat cells but did so in the presence of IκBαM, a transdominant inhibitor of NF-κB. These results suggest that intact, functional NF-κB maintains the survival of activated T cells, and that CD95-induced cleavage of NF-κB subunits sensitizes T cells to apoptosis and, hence, facilitates the decay of an immune response.