University of Stuttgart, Institute of Cell Biology and Immunology, Stuttgart, Germany; University of Stuttgart, Stuttgart Research Center Systems Biology, Stuttgart, Germany.
Department of Biochemistry, University of Stuttgart, Institute of Biochemistry and Technical Biochemistry, Stuttgart, Germany.
Int Rev Cell Mol Biol. 2020;351:57-99. doi: 10.1016/bs.ircmb.2020.02.002. Epub 2020 Mar 2.
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.
细胞因子肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）是 TNF 超家族的一个成员，通过与 TRAIL 受体 1（TRAILR1）和 TRAIL 受体 2（TRAILR2）结合并激活这两个受体，TRAIL 可以在转化或感染的细胞中引发凋亡。与同一家族的其他死亡配体相比，TRAIL 优先在恶性细胞中诱导凋亡，而不影响正常组织，因此已被广泛研究作为抗癌剂的适用性。最近，人们注意到 TRAIL 受体信号也与内质网（ER）应激和未折叠蛋白反应（UPR）有关。因此，TRAIL 受体在调节细胞凋亡易感性方面的作用比以前认为的更为广泛。在这里，我们提供了 TRAIL 诱导信号的概述，涵盖了细胞外凋亡过程中的核心信号转导以及与其他结果（如坏死性凋亡或 NF-κB 激活）的联系。我们讨论了环境因素、转录调节剂以及遗传或表观遗传改变如何调节 TRAIL 受体，从而改变细胞对 TRAIL 的敏感性。最后，我们深入探讨了 TRAIL 受体在涉及未折叠蛋白反应的信号转导场景中的作用，并讨论了这些发现如何转化为癌症治疗的新联合治疗方法。
