E3连接酶CHIP通过调控PERK相关通路影响细胞老化的机制研究

Cellular senescence is the irreversible growth arrest of individual mitotic cells, which as a consequence contributes to ageing and the progression of human diseases. Emerging evidence indicates that endoplasmic reticulum (ER) stress and its downstream unfolded protein response (UPR) are critical in determining the different aspects of the cellular senescence programs. Post-translational modifications of the three major signaling transducers, PERK, IRE1 and ATF6, play key roles in regulating signal transduction events during UPR induction; however, the regulators of these modifications and the underlying regulatory mechanisms have not yet been fully elucidated. Our preliminary data showed that siNRA-mediated knockdown of E3 ligase CHIP induces cellular senescence under ER stress. We also found that CHIP directly interacts with PERK and is essential for the activation of UPR pathway. The central objective of this project is to elucidate the molecular mechanisms of CHIP-involved PERK pathway activation and the roles of CHIP in the cellular senescence. These studies will not only illuminate the molecular details that underlie the biological function of CHIP in cellular senescence, but also will greatly improve our understanding of the interconnections between the UPR signaling, the cellular senescence programs and senescence-related disease progression.

细胞老化是一种不可逆的细胞周期阻滞现象，与生命体的衰老和包括肿瘤在内的多种疾病的发生密切相关。细胞老化进程中，内质网应激及其下游的未折叠蛋白质应答（UPR）信号网络的作用日益凸现。UPR通路的核心起始蛋白分子的翻译后修饰在此通路的活化过程中发挥重要作用，但参与调控的蛋白及调控机制仍有待阐明。已有研究表明E3连接酶CHIP在细胞老化进程中发挥重要作用，我们前期研究发现，CHIP可以与UPR通路起始分子之一的PERK相互作用并促进通路活化，在内质网应激条件下敲低CHIP会促进细胞老化进程。提示CHIP有可能通过泛素化PERK调节PERK相关通路，进而影响细胞老化进程。拟进行的工作将进一步深入探讨CHIP发挥作用的分子机制。该项目不仅有助于阐明CHIP影响细胞老化进程的分子机制，拓展我们对细胞老化复杂进程中的信号网络以及UPR通路调控机制的认识，亦可以为细胞老化相关疾病治疗提供理论依据。

细胞老化是一种不可逆的细胞周期阻滞现象，与生命体的衰老和包括肿瘤在内的多种疾病的发生密切相关。细胞老化进程中，内质网应激及其下游的未折叠蛋白质应答（UPR）信号网络的作用日益凸现。UPR通路的核心起始蛋白分子的翻译后修饰在此通路的活化过程中发挥重要作用，但参与调控的蛋白及调控机制仍有待阐明。已有研究表明E3连接酶CHIP在细胞老化进程中发挥重要作用，我们前期研究发现，CHIP可以与UPR通路起始分子之一的PERK相互作用并促进通路活化，在内质网应激条件下敲低CHIP会促进细胞老化进程。提示CHIP有可能通过泛素化PERK调节PERK相关通路，进而影响细胞老化进程。拟进行的工作将进一步深入探讨CHIP发挥作用的分子机制。该项目不仅有助于阐明CHIP影响细胞老化进程的分子机制，拓展我们对细胞老化复杂进程中的信号网络以及UPR通路调控机制的认识，亦可以为细胞老化相关疾病治疗提供理论依据。