CD30-dependent degradation of TRAF2: implications for negative regulation of TRAF signaling and the control of cell survival
CD30-dependent degradation of TRAF2: implications for negative regulation of TRAF signaling and the control of cell survival
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DOI：
10.1101/gad.11.21.2810
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发表时间：
1997-11-01
影响因子：
10.5
通讯作者：
Thompson, CB
中科院分区：
文献类型：
--
作者：
Duckett, CS;Thompson, CB
CD 30是一种细胞表面受体，可通过诱导转录因子NF-κ B的能力增强淋巴细胞活化和存活。然而，CD 30也参与诱导淋巴细胞的凋亡性细胞死亡。在这里，我们表明，CD 30信号转导的影响之一是使细胞对1型肿瘤坏死因子受体（TNFR 1）诱导的凋亡敏感。这种致敏作用依赖于CD 30胞质结构域内的TRAP结合位点。与这些位点结合的蛋白质之一是TRAF 2，它是一种信号转导分子，也被TNFR 1用来介导几种下游激酶和转录因子的激活。在CD 30信号转导过程中，我们发现TRAF 2与CD 30胞浆结构域的结合导致TRAF 2和相关蛋白TRAF 1通过蛋白水解快速耗尽。这些数据提示了一种模型，其中CD 30通过TRAF 2的信号偶联耗尽来限制其自身抑制细胞存活信号的能力。细胞内TRAF 2及其相关蛋白的消耗也增加了细胞在死亡诱导受体如TNFR 1激活期间经历凋亡的敏感性。与这一假设相一致的是，发现显性阴性形式的TRAF 2的表达增强TNFR 1介导的死亡。这些研究提供了一种潜在的机制，通过这种机制，CD 30以及TNFR超家族的其他TRAP结合成员可以负向调节细胞存活。
CD30 is a cell-surface receptor that can augment lymphocyte activation and survival through its ability to induce the transcription factor NF-KB. CD30, however, has also been implicated in the induction of apoptotic cell death of lymphocytes. Here we show that one of the effects of CD30 signal transduction is to render cells sensitive to apoptosis induced by the type 1 tumor necrosis factor receptor (TNFR1). This sensitization is dependent on the TRAP-binding sites within the CD30 cytoplasmic domain. One of the proteins that binds to these sites is TRAF2, a signal transduction molecule that is also utilized by TNFR1 to mediate the activation of several downstream kinases and transcription factors. During CD30 signal transduction, we found that binding of TRAF2 to the cytoplasmic domain of CD30 results in the rapid depletion of TRAF2 and the associated protein TRAF1 by proteolysis. These data suggest a model in which CD30 limits its own ability to transduce cell survival signals through signal-coupled depletion of TRAF2. Depletion of intracellular TRAF2 and its coassociated proteins also increased the sensitivity of the cell to undergoing apoptosis during activation of death-inducing receptors such as TNFR1. Consistent with this hypothesis, expression of a dominant-negative form of TRAF2 was found to potentiate TNFR1-mediated death. These studies provide a potential mechanism through which CD30, as well as other TRAP-binding members of the TNFR superfamily, can negatively regulate cell survival.