TNFα-induced apoptosis enabled by CCN1/CYR61: pathways of reactive oxygen species generation and cytochrome c release.
TNFα-induced apoptosis enabled by CCN1/CYR61: pathways of reactive oxygen species generation and cytochrome c release.
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DOI：
10.1371/journal.pone.0031303
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lau LF
中科院分区：
文献类型：
--
作者：
Juric V;Chen CC;Lau LF
尽管肿瘤坏死因子α是一种强大的细胞凋亡诱导剂，但它在体外对大多数正常细胞的细胞毒性需要阻断NFκB信号或抑制从头合成蛋白质，典型的方法是添加放线菌酮。然而，CCN(Cyr61/CTGF/Nov)家族的几个成员在体外可以在不抑制NFαB或从头蛋白合成的情况下实现依赖于肿瘤坏死因子κ的细胞凋亡，而CCN1(CyR61)在体内是实现最佳的肿瘤坏死因子α细胞毒性所必需的。以前的研究表明，CCN1通过结合整合素αvα5、β6α1和细胞表面硫酸乙酰肝素蛋白多糖β4来诱导高水平的活性氧积累，导致细胞凋亡所必需的JNK的两相激活，从而揭示了肿瘤坏死因子Syndecan的细胞毒性。在这里，我们首次证明了CCN1与低密度脂蛋白受体相关蛋白1(LRP1)在蛋白质复合体中相互作用，并且与LRP1的结合对于CCN1诱导的ROS的产生以及与肿瘤坏死因子α的凋亡协同作用是至关重要的。我们还发现中性鞘磷脂酶1(NSMase1)参与了ccn1诱导的ROS的产生，是ccn1/肿瘤坏死因子α诱导的细胞凋亡所必需的。此外，CCN1还可促进P53和p38MAPK的激活，从而促进细胞色素c的释放，从而增强肿瘤坏死因子α的细胞毒作用。相反，当环己亚胺促进肿瘤坏死因子α依赖的细胞凋亡时，LRP1、nSMase1、p53和p38MAPK不是必需的，这表明它们在与肿瘤坏死因子α诱导的信号事件汇合的信号通路中发挥作用。由于CCN1/CyR61至少在某些情况下是肿瘤坏死因子α细胞毒性的生理调节因子，这些发现可能揭示肿瘤坏死因子α诱导体内细胞凋亡的重要介质，并确定潜在的治疗靶点以阻止肿瘤坏死因子α依赖的组织损伤。
Although TNFα is a strong inducer of apoptosis, its cytotoxicity in most normal cells in vitro requires blockade of NFκB signaling or inhibition of de novo protein synthesis, typically by the addition of cycloheximide. However, several members of CCN (CYR61/CTGF/NOV) family of extracellular matrix proteins enable TNFα-dependent apoptosis in vitro without inhibiting NFκB or de novo protein synthesis, and CCN1 (CYR61) is essential for optimal TNFα cytotoxicity in vivo. Previous studies showed that CCN1 unmasks the cytotoxicity of TNFα by binding integrins αvβ5, α6β1, and the cell surface heparan sulfate proteoglycan syndecan 4 to induce the accumulation of a high level of reactive oxygen species (ROS), leading to a biphasic activation of JNK necessary for apoptosis. Here we show for the first time that CCN1 interacts with the low density lipoprotein receptor-related protein 1 (LRP1) in a protein complex, and that binding to LRP1 is critical for CCN1-induced ROS generation and apoptotic synergism with TNFα. We also found that neutral sphingomyelinase 1 (nSMase1), which contributes to CCN1-induced ROS generation, is required for CCN1/TNFα-induced apoptosis. Furthermore, CCN1 promotes the activation of p53 and p38 MAPK, which mediate enhanced cytochrome c release to amplify the cytotoxicity of TNFα. By contrast, LRP1, nSMase1, p53, and p38 MAPK are not required when TNFα-dependent apoptosis is facilitated by the presence of cycloheximide, indicating that they function in the CCN1 signaling pathway that converges with TNFα-induced signaling events. Since CCN1/CYR61 is a physiological regulator of TNFα cytotoxicity at least in some contexts, these findings may reveal important mediators of TNFα-induced apoptosis in vivo and identify potential therapeutic targets for thwarting TNFα-dependent tissue damage.
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