The cytokine tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the large TNF superfamily that can trigger apoptosis in transformed or infected cells by binding and activating two receptors, TRAIL receptor 1 (TRAILR1) and TRAIL receptor 2 (TRAILR2). Compared to other death ligands of the same family, TRAIL induces apoptosis preferentially in malignant cells while sparing normal tissue and has therefore been extensively investigated for its suitability as an anti-cancer agent. Recently, it was noticed that TRAIL receptor signaling is also linked to endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). The role of TRAIL receptors in regulating cellular apoptosis susceptibility therefore is broader than previously thought. Here, we provide an overview of TRAIL-induced signaling, covering the core signal transduction during extrinsic apoptosis as well as its link to alternative outcomes, such as necroptosis or NF-κB activation. We discuss how environmental factors, transcriptional regulators, and genetic or epigenetic alterations regulate TRAIL receptors and thus alter cellular TRAIL susceptibility. Finally, we provide insight into the role of TRAIL receptors in signaling scenarios that engage the unfolded protein response and discuss how these findings might be translated into new combination therapies for cancer treatment.

中文翻译：

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TRAIL受体信号转导：从规范信号转导的基本原理开始，直至其与ER应力和未折叠的蛋白质反应纠缠在一起。

细胞因子肿瘤坏死因子（TNF）相关的凋亡诱导配体（TRAIL）是大型TNF超家族的成员，可以通过结合并激活两种受体TRAIL受体1（TRAILR1）和TRAIL受体来触发转化或感染细胞的凋亡。 2（TRAILR2）。与相同家族的其他死亡配体相比，TRAIL在保留正常组织的同时优先诱导恶性细胞凋亡，因此已广泛研究其作为抗癌剂的适用性。最近，注意到TRAIL受体信号转导也与内质网（ER）应激和未折叠的蛋白应答（UPR）有关。因此，TRAIL受体在调节细胞凋亡易感性中的作用比以前认为的要广泛。在这里，我们概述了TRAIL诱导的信号传导，涵盖了外部细胞凋亡过程中的核心信号转导及其与替代结果（如坏死病或NF-κB激活）的联系。我们讨论了环境因素，转录调节因子以及遗传或表观遗传学改变如何调节TRAIL受体，从而改变细胞对TRAIL的敏感性。最后，我们深入了解TRAIL受体在涉及未折叠蛋白应答的信号转导方案中的作用，并讨论如何将这些发现转化为用于癌症治疗的新联合疗法。遗传或表观遗传学改变会调节TRAIL受体，从而改变细胞对TRAIL的敏感性。最后，我们深入了解TRAIL受体在涉及未折叠蛋白应答的信号转导方案中的作用，并讨论如何将这些发现转化为用于癌症治疗的新联合疗法。遗传或表观遗传学改变会调节TRAIL受体，从而改变细胞对TRAIL的敏感性。最后，我们深入了解TRAIL受体在涉及未折叠蛋白应答的信号转导方案中的作用，并讨论如何将这些发现转化为用于癌症治疗的新联合疗法。