IRE1/TRAF2诱导细胞凋亡的分子机制

Molecular Mechanism of Cell Apoptosis Induced by IRE1/TRAF2

在细胞内质网应激中,IRE1/TRAF2/ASK1复合物可激活JNK信号通路,诱导细胞凋亡。IRE1-Lys828可被E3连接酶CHIP泛素化而激活。而TRAF2本身也具有RING结构域的E3泛素连接酶活性,可结合于IRE1的泛素化位点Lys828,促进IRE1磷酸化活化。IRE1/TRAF2复合物可募集ASK1,进而磷酸化激活JNK信号通路。另外,IRE1/TRAF2也可激活MAPK/p38、NF-κB以及caspase-12等信号途径,促进细胞凋亡。ASK1也是内质网应激IRE1/TRAF2诱导激活细胞凋亡所必需的。因此,TRAF2在调控细胞内质网应激,激活IRE1途径,诱导细胞凋亡中具有重要的作用,可作为一个靶点进行药物开发。

IRE1/TRAF2/ASK1 compounds can activate JNK signal pathway and lead to cell apoptosis under the endoplasmic reticulum（ER） stress. IRE1-Lys828 can be ubiquitinated and activated by E3 ligase CHIP. TRAF2 itself also has the E3 ubiquitin ligase activity of RING domain, which can bind to Lys828, the ubiquitinated site of IRE1 and promote the activation of IRE1 phosphorylation. Subsequently, IRE1/TRAF2 compounds can recruit ASK1, then phosphorylate and activate JNK signal pathway. In addition, IRE1/TRAF2 can also activate signal pathways of MAPK/p38, NF-κB, and caspase-12, and promote cell apoptosis. ASK1 is an essential factor for IRE1/TRAF2 signaling to activate apoptosis under ER stress. Thus, TRAF2 plays an important role in regulating ER stress, activating IRE1 pathway and inducing cell apoptosis. TRAF2 might be used as a target for drug development.