Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis
Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis
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DOI：
10.1073/pnas.0507329102
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发表时间：
2005-12-13
影响因子：
11.1
通讯作者：
Chan, FKM
中科院分区：
文献类型：
--
作者：
Clancy, L;Mruk, K;Chan, FKM
肿瘤坏死因子 (TNF) 相关凋亡诱导配体 (TRAIL) 是一种具有潜在治疗癌症价值的细胞因子，因为它对许多转化细胞而非正常细胞具有选择性细胞毒性。 “诱饵受体”TRAIL-R3（TR3）和TRAIL-R4（TR4）被认为通过与TRAIL-R1（TR1）和TRAIL-R2（TR2）竞争配体结合来负调节TRAIL诱导的细胞毒性。在这里，我们表明 TR4 对 TRAIL 诱导的细胞凋亡的抑制关键取决于它通过与两个受体的第一个部分富含半胱氨酸的结构域重叠的 NH2 末端前配体组装结构域与 TR2 的关联。相比之下，TR4的配体结合对于其凋亡抑制功能来说是可有可无的，从而排除了TR4是通过结合TRAIL来抑制凋亡的“诱饵”的可能性。在仅表达TR2和TR4并且对TRAIL诱导的细胞凋亡具有抵抗力的原代CD8(+)T细胞中，佛波醇肉豆蔻酸酯乙酸酯的刺激消除了TR2和TR4之间的配体非依赖性相互作用，并增强了它们对TRAIL诱导的细胞凋亡的敏感性。因此，虽然大多数 TNF 受体通常仅形成同源三聚体复合物，但 TR2 和 TR4 中的前配体组装结构域允许混合复合物形成，作为调节细胞凋亡诱导的手段。我们认为 TR4 是一种“调节”而非“诱饵”受体，它通过这种先前未表征的配体独立机制抑制 TRAIL 的细胞凋亡信号传导。
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a cytokine with potential therapeutic value against cancers because of its selective cytotoxicity to many transformed, but not normal, cells. The "decoy receptors" TRAIL-R3 (TR3) and TRAIL-R4 (TR4) were believed to negatively regulate TRAIL-induced cytotoxicity by competing for ligand binding with TRAIL-R1 (TR1) and TRAIL-R2 (TR2). Here, we show that inhibition of TRAIL-induced apoptosis by TR4 critically depends on its association with TR2 via the NH2-terminal preligand assembly domain overlapping the first partial cysteine-rich domain of both receptors. By contrast, ligand binding by TR4 is dispensable for its apoptosis inhibitory function, thereby excluding the possibility that TR4 was a "decoy" to inhibit apoptosis by binding up TRAIL. In primary CD8(+) T cells, which express only TR2 and TR4 and are resistant to TRAIL-induced apoptosis, stimulation with phorbol myristate acetate abrogated the ligand-independent interaction between TR2 and TR4 and enhanced their sensitivity to TRAIL-induced apoptosis. Hence, whereas most TNF receptors normally form only homotrimeric complexes, the preligand assembly domains in TR2 and TR4 permit mixed complex formation as a means to regulate apoptosis induction. We propose that TR4 is a "regulatory" rather than "decoy" receptor that inhibits apoptosis signaling by TRAIL through this previously uncharacterized ligand-independent mechanism.