Soluble Extracellular Domain of Death Receptor 5 Inhibits TRAIL-Induced Apoptosis by Disrupting Receptor-Receptor Interactions.
Soluble Extracellular Domain of Death Receptor 5 Inhibits TRAIL-Induced Apoptosis by Disrupting Receptor-Receptor Interactions.
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死亡受体 5 的可溶性胞外结构域通过破坏受体-受体相互作用来抑制 TRAIL 诱导的细胞凋亡。
DOI：
10.1016/j.jmb.2017.08.009
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发表时间：
2017
影响因子：
5.6
通讯作者：
Sachs,JonathanN
中科院分区：
文献类型：
--
作者：
Vunnam,Nagamani;Lo,ChihHung;Grant,BenjaminD;Thomas,DavidD;Sachs,JonathanN
肿瘤坏死因子（TNF）受体信号的失调是各种炎症性疾病的一个关键特征。目前对tnf相关疾病的治疗要么是通过隔离配体，要么是阻断配体与受体的相互作用，这可能会通过抑制与疾病状况无关的受体而产生危险的副作用。因此，需要针对受体-受体相互作用的替代策略。我们假设死亡受体5 （DR5）长异构体的可溶性胞外结构域（ECD）可以阻断内源性受体组装，模拟缺乏死亡结构域的诱饵受体触发细胞凋亡的生物学效应。通过活细胞荧光共振能量转移研究，我们证明了可溶性ECD破坏内源性DR5-DR5相互作用。细胞活力测定证实了ECD完全抑制tnf相关凋亡诱导配体（TRAIL）诱导的细胞凋亡，尽管TRAIL仍然能够与受体结合。重要的是，我们使用诱变技术来证明，ECD对trail诱导的细胞凋亡的抑制主要来自于DR5寡聚化的破坏，而不是配体的隔离。抑制死亡受体的激活在非酒精性脂肪肝等疾病中具有重要的治疗应用。更一般地说，这种方法应该推广到能够抑制与广泛临床条件相关的其他TNF受体信号机制。
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.
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影响因子：
56.9
作者：
Siegel, RM;Frederiksen, JK;Lenardo, MJ
通讯作者：
Lenardo, MJ
影响因子：
4.4
作者：
Zalevsky, Jonathan;Secher, Thomas;Szymkowski, David E.
通讯作者：
Szymkowski, David E.
DOI：
--
发表时间：
2010
期刊：
International journal of biochemistry and molecular biology
影响因子：
--
作者：
S. Park;Khadijeh Bijangi‐Vishehsaraei;A. Safa
通讯作者：
S. Park;Khadijeh Bijangi‐Vishehsaraei;A. Safa
DOI：
10.1016/j.bbrc.2005.03.101
发表时间：
2005-05-20
影响因子：
3.1
作者：
Lee, HW;Lee, SH;Kim, YS
通讯作者：
Kim, YS
DOI：
10.1073/pnas.0507329102
发表时间：
2005-12-13
影响因子：
11.1
作者：
Clancy, L;Mruk, K;Chan, FKM
通讯作者：
Chan, FKM