Laboratory of Molecular Neuropathology, Department of Neurobiology, Key Laboratory of Brain Function and Disease and School of Life Sciences, University of Science & Technology of China, Chinese Academy of Sciences, Hefei, Anhui, PR China.
Oncogene. 2012 Mar 8;31(10):1311-22. doi: 10.1038/onc.2011.315. Epub 2011 Jul 25.
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.
DJ-1 最初被鉴定为一种癌基因产物，与 Ras 合作参与人类肿瘤的发生。在许多癌症中，DJ-1 表达的增加与肿瘤发生有关，而 DJ-1 功能的丧失与常染色体隐性帕金森病（PD）有关。据报道，DJ-1 可保护细胞免受 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不清楚。在这里，我们表明 DJ-1 通过阻断 Fas 相关蛋白死亡结构域（FADD）介导的前胱天蛋白酶-8 激活来抑制 TRAIL 诱导的细胞凋亡。野生型 DJ-1，但不是与 PD 相关的突变 L166P，与 FADD 结合以抑制诱导死亡信号复合物（DISC）的形成。DJ-1 与前胱天蛋白酶-8 在死亡效应结构域竞争结合 FADD，从而抑制前胱天蛋白酶-8 向胱天蛋白酶-8 的活性形式的募集和激活。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。
