Role of RGS2 in the Integrated Stress Response

当细胞生病或受损时，它的新陈代谢会以各种方式改变，以促进恢复和生存。然而，如果恢复不可能或将导致其变得异常，不健康的细胞将通过称为凋亡的过程自我毁灭。无论哪种方式，单个细胞对损伤的反应通常会促进它所属的生物体的长期生存能力。在细胞中，促生存和促凋亡的反应都是由一个被称为综合应激反应的协调变化程序引起的。这些不同的变化可能是有益的，也可能是有害的，或者两者兼而有之，而它们是如何平衡以使细胞继续生存或导致细胞死亡的，目前还不清楚。******我们提出的研究重点是一种叫做RGS2的蛋白质（G蛋白信号2的调节剂），我们和其他人已经证明，在化学或物理损伤引起的细胞损伤时，RGS2会增加。RGS2在综合应激反应中的具体作用尚不清楚，尽管我们的研究结果表明它可能有助于细胞恢复和凋亡。我们之前报道过RGS2与细胞蛋白质合成机制结合，这降低了蛋白质合成的总体速度，从而节省了细胞资源，可以重新定向到生存。最近，我们发现了证据表明后一种效应伴随着rgs2诱导的应激蛋白ATF4（激活转录因子4）和CHOP （C/EBP同源蛋白）的增加。ATF4和CHOP都是在压力时期选择性产生的一组越来越被认识的蛋白质，它们反过来可以触发多种生存和凋亡的生化级联反应。我们假设RGS2还可以促进其他应激蛋白的合成，总的来说，这些变化将导致细胞存活或凋亡，这取决于细胞类型以及所遇到的应激的性质和严重程度。总的来说，本次申请的实验将进一步加深我们对细胞如何应对应激的理解，并阐明RGS2在这一过程中的具体功能。

When a cell becomes sick or damaged, its metabolism is altered in various ways to promote recovery and survival. If recovery is not possible or will lead to it becoming abnormal, however, the unhealthy cell will self-destruct through a process known as apoptosis. Either way, the reaction of an individual cell to damage generally promotes the long-term viability of the living organism that it belongs to. In the cell, both pro-survival and pro-apoptosis reactions arise from a coordinated program of changes referred to as the Integrated Stress Response. These various changes may be beneficial, destructive, or both, and how they balance out to allow the cell to continue living or alternatively bring about its death is not well understood. ******The proposed studies focus on a protein called RGS2 (regulator of G protein signaling 2), which we and others have shown to be increased in response to cellular damage caused by chemical or physical insults. The specific role of RGS2 in the Integrated Stress Response is unknown, although our findings to date suggest that it may contribute to both cell recovery and apoptosis. We previously reported that RGS2 binds to the cellular protein synthesis machinery, which decreases the overall rate of protein synthesis and thereby spares cellular resources that can be redirected towards survival. More recently, we have uncovered evidence that the latter effect is accompanied by RGS2-induced increases in the stress proteins ATF4 (activating transcription factor 4) and CHOP (C/EBP homologous protein). ATF4 and CHOP both are among an increasingly recognized group of proteins that are selectively made during times of stress, and they in turn can trigger multiple survival and apoptotic biochemical cascades. We hypothesize that RGS2 can additionally promote the synthesis of other such stress proteins, and that on balance these changes will lead to either cell survival or apoptosis, depending upon the cell type as well as the nature and the severity of the stress encountered. Overall, the experiments outlined in this Discovery Grant application will further our general understanding of how cells respond to stress and also elucidate the specific functions of RGS2 in this process.