Rapid CD40-mediated rescue from CD95-induced apoptosis requires TNFR-associated factor-6 and PI3K
Rapid CD40-mediated rescue from CD95-induced apoptosis requires TNFR-associated factor-6 and PI3K
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DOI：
10.1002/eji.200535483
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发表时间：
2006-09-01
影响因子：
5.4
通讯作者：
Bishop, Gail A.
中科院分区：
文献类型：
--
作者：
Benson, Rebecca J.;Hostager, Bruce S.;Bishop, Gail A.
活化分子CD 40和死亡受体CD 95/Fas在调节B细胞中起重要作用，从而在没有自身免疫的情况下发生有效的抗微生物免疫。CD 40信号传导增加CD 95表达，使细胞对凋亡敏感，但持续的CD 40信号使B细胞免于CD 95杀伤。在这里，我们描述了早期CD 40介导的CD 95诱导的B细胞凋亡的救援机制。当在启动CD 95凋亡的1- 2小时内给予CD 40信号时，实现了最大的拯救。CD 40信号传导并不阻断Fas相关死亡结构域蛋白与CD 95的结合，但降低了CD 95诱导的caspase 3和8的活化。快速CD 40拯救不需要NF-κ B活化，并且不依赖于从头蛋白质合成，但依赖于活性PI 3 K。通过不结合TNFR相关因子（TRAF）1、TRAF 2和TRAF 3的CD 40突变体发出信号，可将B细胞从CD 95诱导的细胞凋亡中拯救出来。在通过基因靶向使这些TRAF分子缺陷的B细胞系中证实了TRAF 1/2/3-非依赖性拯救。相反，在TRAF 6缺陷型B细胞中，CD 40拯救被完全废除，其显示响应于CD 40接合的Akt活化减少。这些结果揭示了平衡B细胞活化和凋亡的新的快速机制。
The activation molecule CD40 and the death receptor CD95/Fas play important roles in regulating B cells so that effective antimicrobial immunity occurs without auto-immunity. CD40 signaling increases CD95 expression, sensitizing cells to apoptosis, but sustained CD40 signals rescue B cells from CD95 killing. Here we describe a mechanism of early CD40-mediated rescue from CD95-induced apoptosis in B cells. Maximal rescue was achieved when CD40 signals were given within 1-2h of initiating CD95 apoptosis. CD40 signaling did not block association of Fas-associated death domain-containing protein with CD95, but decreased CD95-induced activation of caspases 3 and 8. Rapid CD40 rescue did not require NF-kappa B activation and was independent of de novo protein synthesis, but was dependent upon active PI3K. Signaling via a CD40 mutant that does not bind TNFR-associated factor (TRAF)1, TRAF2, and TRAF3 rescued B cells from CD95-induced apoptosis. TRAF1/2/3-independent rescue was confirmed in B cell lines made deficient in these TRAF molecules by gene targeting. In contrast, CD40 rescue was completely abrogated in TRAF6-deficient B cells, which showed reduced activation of Akt in response to CD40 engagement. These results reveal a new rapid mechanism to balance B cell activation and apoptosis.