Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway
Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway
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孤儿核受体TR3通过线粒体信号通路参与自噬细胞死亡
DOI：
10.1038/nchembio.1406
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发表时间：
2014-02-01
影响因子：
14.8
通讯作者：
Wu, Qiao
中科院分区：
文献类型：
--
作者：
Wang, Wei-jia;Wang, Yuan;Wu, Qiao
自噬与细胞死亡有关，但相关机制在很大程度上尚未得到充分表征。我们发现，黑色素瘤通常对药物诱导的细胞凋亡具有抵抗力，但在孤儿核受体TR3的参与下，可以发生自噬性细胞死亡。导致细胞死亡的一系列分子事件是由一种特定的化合物 1-(3,4,5-三羟基苯基)nonan-1-one 启动的，该化合物是从 TR3 靶向化合物库的筛选中新获得的。自噬级联包括 TR3 通过与线粒体外膜蛋白 Nix 相互作用易位到线粒体，通过 Tom40 和 Tom70 通道蛋白进入线粒体内膜，通透性转换孔复合物 ANT1-VDAC1 耗散线粒体膜电位并诱导自噬。这个过程导致线粒体过度清除和不可逆的细胞死亡。它暗示了一种通过激活线粒体信号通路来治疗黑色素瘤的新方法，该通路将核受体与细胞死亡的自噬结合起来。
Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.