铜绿假单胞菌 ExoS 毒素蛋白诱导的细胞凋亡信号通路研究

铜绿假单胞菌所编码的毒素蛋白 ExoS 能够高效地诱导多种宿主细胞的凋亡。ExoS 通过其 ADP 核糖转移酶活性来激活JNK介导内源性凋亡通路，同时还抑制 ERK 信号通路介导的存活途径。ExoS 通过 ADP 糖基化 Ras 蛋白来抑制 ERK 信号通路, 而其激活 JNK 信号通路的分子机理尚不清楚。有趣的是, G1 期细胞对 ExoS 引起的凋亡比其他周期的细胞更为敏感。 在本项目申请中, 我们拟确定 ExoS 诱导凋亡途径的最关键成分，也就是 ExoS 的底物蛋白。然后, 我们将对 ExoS 介导的细胞凋亡与细胞周期的相关性机理进行研究。 对 ExoS 介导的凋亡途径的研究能为细胞凋亡调节途径提供新的观点, 进而为靶向诱导细胞凋亡治疗癌症提供新的途径。

Pseudomonas aeruginosa encoded cytotoxin, ExoS, can induce apoptosis efficiently in a variety of host cells. The ExoS has an ADP-ribosylating activity which not only triggers apoptosis through JNK activation, but also inhibits the cell survival pathway through inhibition of ERK signaling pathway. The later effect is through ADP-ribosylation of Ras protein, however, the ExoS substrate responsible for the activation of the JNK signaling pathway is not known. Another interesting observation relates to G1 phase cells being much more sensitive to the ExoS induced apoptosis than those in other cell cycle phases. In this project, we intend to identify and characterize the ExoS substrate which triggers the apoptotic signaling. Then, we will further study the mechanism by which cell cycle influences the ExoS-mediated apoptosis. These studies will provide a new perspective on apoptosis regulation and thus provide new strategies for the targeted killing of cancer cells.