DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD
DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD
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DJ-1 通过阻止 pro-caspase-8 募集到 FADD 来抑制 TRAIL 诱导的细胞凋亡
DOI：
10.1038/onc.2011.315
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发表时间：
2012-03-01
期刊：
影响因子：
8
通讯作者：
Wang, G.
中科院分区：
文献类型：
--
作者：
Fu, K.;Ren, H.;Wang, G.
DJ-1最初被鉴定为与Ras合作参与人类肿瘤发生的癌基因产物。DJ-1表达的增加与许多癌症中的肿瘤发生相关，而DJ-1功能的丧失与帕金森病（PD）的常染色体隐性形式有关。据报道，DJ-1保护细胞免于TRAIL（肿瘤坏死因子相关凋亡诱导配体）诱导的凋亡。然而，DJ-1参与的机制在很大程度上仍然未知。在这里，我们表明，DJ-1抑制TRAIL诱导的细胞凋亡，通过阻断Fas相关蛋白死亡结构域（FADD）介导的caspase-8激活。野生型DJ-1，而不是PD相关突变体L166 P，结合FADD以抑制死亡诱导信号复合物（DISC）的形成。DJ-1与胱天蛋白酶原-8竞争结合至死亡效应结构域处的FADD，从而抑制胱天蛋白酶原-8向胱天蛋白酶-8的活性形式的募集和活化。因此，我们的研究表明，DJ-1通过调节DISC的形成来防止TRAIL诱导的细胞凋亡。
DJ-1 was initially identified as an oncogene product involved in human tumorigenesis in cooperation with Ras. Increased DJ-1 expression is associated with tumorigenesis in many cancers, whereas the loss of DJ-1 function is linked to an autosomal recessive form of Parkinson's disease (PD). It has been reported that DJ-1 protects cells from TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis. However, the mechanism by which DJ-1 is involved is still largely unknown. Here we show that DJ-1 inhibits TRAIL-induced apoptosis by blocking Fas-associated protein death domain (FADD)-mediated pro-caspase-8 activation. Wild-type DJ-1, but not the PD-associated mutant L166P, binds to FADD to inhibit the formation of the death-inducing signaling complex (DISC). DJ-1 competes with pro-caspase-8 to bind to FADD at the death effector domain, thereby repressing the recruitment and activation of pro-caspase-8 to the active form of caspase-8. Thus, our study suggests that DJ-1 protects against TRAIL-induced apoptosis through the regulation of DISC formation.