Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2
Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2
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DOI：
10.1128/mcb.00520-06
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发表时间：
2006-10-01
影响因子：
5.3
通讯作者：
Micheau, Olivier
中科院分区：
文献类型：
--
作者：
Merino, Delphine;Lalaoui, Najoua;Micheau, Olivier
肿瘤坏死因子相关的凋亡诱导配体(TRAIL)是肿瘤坏死因子家族的一员，具有一定的选择性，可通过细胞凋亡诱导肿瘤细胞死亡。TRAIL诱导的细胞凋亡是由跨膜受体死亡受体4(DR4)(又称TRAIL-R1)和DR5(TRAIL-R2)介导的。TRAIL还可以结合诱骗受体1(DcR1)(TRAIL-R3)和DcR2(TRAIL-R4)，因为它们分别缺乏和截断细胞质死亡结构域而无法诱导细胞凋亡。此外，DcR1和DcR2抑制DR4和DR5介导的TRAIL诱导的细胞凋亡，我们在这里证明了这是通过不同的机制发生的。虽然DcR1通过滴定TRAIL在脂筏内阻止死亡诱导信号复合体(DISC)的组装，但DcR2与DR5在DCR2内共招募，在那里它抑制启动子caspase的激活。此外，DcR2可防止DR5光盘中的DR4招募。DcR1和DcR2介导的TRAIL抑制的特异性揭示了TRAIL信号调节的额外复杂性。
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that induces cancer cell death by apoptosis with some selectivity. TRAIL-induced apoptosis is mediated by the transmembrane receptors death receptor 4 (DR4) (also known as TRAIL-R1) and DR5 (TRAIL-R2). TRAIL can also bind decoy receptor 1 (DcR1) (TRAIL-R3) and DcR2 (TRAIL-R4) that fail to induce apoptosis since they lack and have a truncated cytoplasmic death domain, respectively. In addition, DcR1 and DcR2 inhibit DR4- and DR5-mediated, TRAIL-induced apoptosis and we demonstrate here that this occurs through distinct mechanisms. While DcR1 prevents the assembly of the death-inducing signaling complex (DISC) by titrating TRAIL within lipid rafts, DcR2 is corecruited with DR5 within the DISC, where it inhibits initiator caspase activation. In addition, DcR2 prevents DR4 recruitment within the DR5 DISC. The specificity of DcR1- and DcR2-mediated TRAIL inhibition reveals an additional level of complexity for the regulation of TRAIL signaling.