Indirubin Inhibits TRAIL-Induced Activation of Death Receptor 5 in Jurkat Cells.
Indirubin Inhibits TRAIL-Induced Activation of Death Receptor 5 in Jurkat Cells.
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DOI：
10.1177/1934578x221144580
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发表时间：
2023-01
影响因子：
1.8
通讯作者：
Sachs, Jonathan N. N.
中科院分区：
文献类型：
--
作者：
Young, Malaney C. C.;Vunnam, Nagamani;Rebbeck, Robyn T. T.;Yuen, Samantha L. L.;Thomas, David D. D.;Sachs, Jonathan N. N.
死亡受体5(Death Receptor 5，DR5)是一种诱导细胞凋亡的膜受体，在多种威胁生命的条件下介导细胞死亡。目前迫切需要发现DR5受体拮抗剂，用于治疗DR5过度激活是其病理生理基础的条件。在非酒精性脂肪性肝病和包括淀粉样β蛋白(Aβ)蓄积、脊髓损伤(SCI)和脑缺血在内的神经退行性变过程中，DR5的激活介导了细胞死亡。在目前的工作中，我们使用荧光共振能量转移(FRET)来监测介导死亡信号的DR5的构象动力学。我们使用时间分辨FRET筛选平台对美国食品和药物管理局(FDA)批准的2863种化合物的Selleck库进行筛选。高通量筛选(HTS)鉴定出13种化合物，它们调节DR5单体之间的FRET，偏离DMSO对照的中位数绝对偏差(MAD)超过5。在这13个化合物中，靛玉红被鉴定为特异性地抑制肿瘤坏死因子相关的凋亡诱导配体(TRAIL)诱导的caspase-8活性，而不调节DR5的表面表达或TRAIL的结合。抑制Fas相关死亡结构域(FADD)寡聚和增加细胞内FLICE抑制蛋白(c-FliP)的表达是抑制DR5信号级联反应的分子机制。这项研究阐明了以前未知的靛玉红属性，使其成为治疗研究DR5过度激活的疾病的有希望的候选药物。
Death receptor 5 (DR5) is an apoptosis-inducing membrane receptor that mediates cell death in several life-threatening conditions. There is a crucial need for the discovery of DR5 antagonists for the therapeutic intervention of conditions in which the overactivation of DR5 underlies the pathophysiology. DR5 activation mediates cell death in non-alcoholic fatty liver disease (NAFLD) and neurodegenerative processes including amyloid-beta (Aβ) accumulation, spinal cord injury (SCI), and brain ischemia. In the current work, we used fluorescence resonance energy transfer (FRET) to monitor the conformational dynamics of DR5 that mediate death signaling. We used a time-resolved FRET screening platform to screen the Selleck library of 2863 U.S. Food and Drug Administration (FDA)-approved compounds. The high-throughput screen (HTS) identified 13 compounds that modulated the FRET between DR5 monomers beyond 5 median absolute deviations (MADs) from the DMSO controls. Of these 13 compounds, indirubin was identified to specifically inhibit tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced caspase-8 activity without modulating DR5 surface expression or TRAIL binding. Indirubin inhibited Fas-associated death domain (FADD) oligomerization and increased cellular FLICE-inhibitory protein (c-FLIP) expression; both are molecular mechanisms involved in inhibiting the DR5 signaling cascade. This study has elucidated previously unknown properties of indirubin that make it a promising candidate for therapeutic investigation of diseases in which overactivation of DR5 underlies pathology.
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影响因子：
--
作者：
Gruber SJ;Cornea RL;Li J;Peterson KC;Schaaf TM;Gillispie GD;Dahl R;Zsebo KM;Robia SL;Thomas DD
通讯作者：
Thomas DD
影响因子：
18.4
作者：
Deng D;Shah K
通讯作者：
Shah K
影响因子：
6.3
作者：
Akazawa Y;Nakao K
通讯作者：
Nakao K
DOI：
10.1016/j.jbc.2021.100840
发表时间：
2021-07
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Bunch TA;Guhathakurta P;Lepak VC;Thompson AR;Kanassatega RS;Wilson A;Thomas DD;Colson BA
通讯作者：
Colson BA
影响因子：
24.5
作者：
Haag, Christian;Stadel, Dominic;Fulda, Simone
通讯作者：
Fulda, Simone