Role of RGS2 in the Integrated Stress Response

当一个细胞生病或受损时，它的新陈代谢会以各种方式改变，以促进恢复和存活。如果恢复是不可能的，或者将导致它变得异常，然而，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都会促进其所属的生物体的长期生存能力。在细胞中，促存活和促凋亡反应都是由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，破坏性的，或两者兼而有之，它们如何平衡以允许细胞继续生存或导致其死亡还不清楚。** 拟议的研究集中在一种名为RGS 2（G蛋白信号转导调节因子2）的蛋白质上，我们和其他人已经证明，这种蛋白质在对化学或物理损伤引起的细胞损伤做出反应时会增加。RGS 2在综合应激反应中的具体作用尚不清楚，尽管我们迄今的研究结果表明它可能有助于细胞恢复和凋亡。我们以前报道过RGS 2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率，从而节省了可以重新定向用于生存的细胞资源。最近，我们发现的证据表明，后者的影响是伴随着RGS 2诱导的应激蛋白ATF 4（激活转录因子4）和CHOP（C/EBP同源蛋白）的增加。ATF 4和CHOP都是越来越多地被认可的蛋白质组，它们在应激期间选择性地产生，并且它们反过来可以触发多个存活和凋亡生化级联反应。我们假设RGS 2可以另外促进其他此类应激蛋白的合成，并且平衡地，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，这项发现资助申请中概述的实验将进一步加深我们对细胞如何应对压力的一般理解，并阐明RGS 2在这一过程中的特定功能。

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.