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首页> 外文期刊>Journal of Molecular Biology >Soluble Extracellular Domain of Death Receptor 5 Inhibits TRAIL-Induced Apoptosis by Disrupting Receptor Receptor Interactions
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Soluble Extracellular Domain of Death Receptor 5 Inhibits TRAIL-Induced Apoptosis by Disrupting Receptor Receptor Interactions

机译：死亡受体5的可溶性细胞外结构域通过破坏受体受体相互作用来抑制血迹诱导的细胞凋亡

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Dysregulation of tumor necrosis factor (TNF) receptor signaling is a key feature of various inflammatory disorders. Current treatments for TNF-related diseases function either by sequestering ligand or blocking ligand receptor interactions, which can cause dangerous side effects by inhibiting the receptors that are not involved in the disease condition. Thus, alternate strategies that target receptor receptor interactions are needed. We hypothesized that the soluble extracellular domain (ECD) of long isoform of death receptor 5 (DR5) could block endogenous receptor assembly, mimicking the biological effect of decoy receptors that lack the death domain to trigger apoptosis. Using live-cell fluorescence resonance energy transfer studies, we demonstrated that soluble ECD disrupts endogenous DR5 DR5 interactions. Cell viability assays were used to demonstrate the complete inhibition of TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by the ECD, although TRAIL is still able to bind to the receptor. Importantly, we used mutagenesis to prove that the inhibition of TRAIL-induced apoptosis by the ECD predominantly comes from the disruption of DR5 oligomerization and not ligand sequestration. Inhibition of death receptor activation should have important therapeutic applications in diseases such as nonalcoholic fatty liver disease. More generally, this approach should be generalized to enable the inhibition of other TNF receptor signaling mechanisms that are associated in a wide range of clinical conditions. (C) 2017 Published by Elsevier Ltd.
机译：肿瘤坏死因子（TNF）受体信号传导的失调是各种炎症障碍的关键特征。通过抑制不涉及疾病病症的受体，通过螯合配体或阻断配体受体相互作用的TNF相关疾病的当前处理功能均可引起危险的副作用。因此，需要靶向受体受体相互作用的替代策略。我们假设死亡受体5（DR5）长同同型（DR5）的可溶性细胞外结构域（ECD）可以阻断内源性受体组装，模拟缺乏死亡域的诱饵受体的生物学效果以引发凋亡。使用活细胞荧光共振能量转移研究，我们证明可溶性ECD破坏内源性DR5 DR5相互作用。使用细胞活力测定来证明ECD的TNF相关凋亡诱导配体（TRAP）诱导的细胞凋亡的完全抑制，尽管径仍然能够与受体结合。重要的是，我们使用诱变来证明ECD的抑制诱导的细胞凋亡主要来自DR5寡聚的破坏而不是配体螯合。死亡受体激活的抑制应具有重要的治疗应用在诸如非酒精性脂肪肝疾病等疾病中。更一般地，应该推广该方法以使得能够抑制在各种临床条件下相关的TNF受体信号传导机制。 （c）2017年由elestvier有限公司出版

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