程序性细胞坏死(Necroptosis)是不同于细胞凋亡(Apoptosis)的一种新的细胞程序性死亡方式。RIpK1、RIpK3 和MLKL蛋白是TNF(肿瘤坏死因子) 引起的程序性细胞坏死通路中的关键信号蛋白。在TNF刺激诱导下，RIpK1和RIpK3结合组装形成Necrosome蛋白信号复合体，Necrosome形成后对MLKL蛋白磷酸化，促使其多聚并转移到细胞膜，启动程序性细胞坏死(Necroptosis).

张四清实验室发现Hsp90调控TNF诱导的程序性细胞坏死。Hsp90稳定程序性细胞坏死的关键蛋白MLKL并调控其结构，促进MLKL多聚及细胞膜转移，增强MLKL引起的细胞坏死。研究发现一种Hsp90的特异小分子抑制化合物17AAG可以阻断TNF引起的细胞坏死，说明Hsp90为TNF刺激的细胞坏死所必需。张四清实验室的发现有助于深入了解程序性细胞坏死(Necroptosis)的调控机制及其在许多疾病中的作用。

研究成果于2月11日在线发表于Cell Death & Disease期刊。通讯作者张四清教授；博士生赵辛萌、研究生陈震、赵稼宝和张盼盼为主要作者。


原文摘要：

Hsp90 modulates the stability of MLKL and is required for TNF-induced necroptosis

The pseudokinase mixed lineage kinase domain-like protein (MLKL) is a key component of tumor necrosis factor (TNF)-induced necroptosis and plays a crucial role in necroptosis execution. However, the mechanisms that control MLKL activity are not completely understood. Here, we identify the molecular chaperone Hsp90 as a novel MLKL-interacting protein. We show that Hsp90 associates with MLKL and is required for MLKL stability. Moreover, we find that Hsp90 also regulates the stability of the upstream RIp3 kinase. Interference with Hsp90 function with the 17AAG inhibitor destabilizes MLKL and RIp3, resulting in their degradation by the proteasome pathway. Furthermore, we find that Hsp90 is required for TNF-stimulated necrosome assembly. Disruption of Hsp90 function prevents necrosome formation and strongly reduces MLKL phosphorylation and inhibits TNF-induced necroptosis. Consistent with a positive role of Hsp90 in necroptosis, coexpression of Hsp90 increases MLKL oligomerization and plasma membrane translocation and enhances MLKL-mediated necroptosis. Our findings demonstrate that an efficient necrotic response requires a functional Hsp90.