CD95 (Fas)-induced caspase-mediated proteolysis of NF-kappaB.
CD95 (Fas)-induced caspase-mediated proteolysis of NF-kappaB.
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发表时间：
1998
期刊：
影响因子：
11.2
通讯作者：
R. Ravi;A. Bedi;E. Fuchs
中科院分区：
文献类型：
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作者：
R. Ravi;A. Bedi;E. Fuchs
核因子 (NF)-kappaB 转录因子的激活有助于免疫反应和外周激活 T 细胞的存活。我们证明，CD95 (Fas/APO1)（淋巴细胞中一种有效的细胞凋亡刺激物）的连接，通过诱导 NF-kappaB p65 (Rel A) 和 p50 的蛋白水解裂解，导致 Jurkat T 细胞中 NF-kappaB 活性的抑制。通过特定的乙酰化醛 (Ac-DEVD-CHO) 对 caspase-3 相关蛋白酶的抑制可防止 CD95 诱导的 p65 (RelA) 或 p50 裂解，并恢复用抗 CD95 抗体处理的细胞中 NF-κB 的诱导能力。添加重组 caspase-3 也会在体外导致 RelA p65 和 p50 的蛋白水解裂解。与 CD95 连接不同，TNF-α 治疗不会导致 Jurkat 细胞死亡，但在 I kappaB αM（一种 NF-kappaB 反式显性抑制剂）存在的情况下会导致 Jurkat 细胞死亡。这些结果表明，完整的、功能性的 NF-κB 维持活化 T 细胞的存活，并且 CD95 诱导的 NF-κB 亚基裂解使 T 细胞对细胞凋亡敏感，因此促进免疫反应的衰减。
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.