The control of mRNA fate during cellular stress

综合应力响应（ISR）的一个基本组成部分是可逆的平移抑制。这种mRNA沉默发生在称为应激颗粒（SGs）的不同细胞质灶中，该灶与加工体（PBs）短暂相关，通常作为mRNA衰变中心。mrna是如何在SGs中免受降解的，这在很大程度上仍然是难以捉摸的。在最近的研究中，我们发现rna结合的zipcode结合蛋白1 （ZBP1）通常参与调节非应激细胞中特定mRNA的细胞质命运，在ISR期间定位到SGs时是mRNA周转的关键调节剂。ZBP1与SGs中靶mrna的关联并不是mrna靶向这些细胞质灶所必需的。然而，在ISR过程中，ZBP1敲除诱导了目标mRNA的选择性不稳定，而强制表达增加了mRNA的稳定性。根据所提出的项目，我们的目标是确定定位于SGs的ZBP1和其他rna结合蛋白在ISR期间促进mRNA命运调节的分子网络。这些的鉴定将为描述细胞应激过程中rna结合蛋白如何控制rna代谢奠定基础。

An essential constituent of the integrated stress response (ISR) is a reversible translational suppression. This mRNA silencing occurs in distinct cytoplasmic foci called stress granules (SGs) that transiently associate with processing bodies (PBs) typically serving as mRNA decay centers. How mRNAs are protected from degradation in SGs remains largely elusive. In recent studies we discovered that the RNA-binding Zipcode-binding protein 1 (ZBP1), typically involved in regulating the cytoplasmic fate of specific mRNAs in nonstressed cells, is a key regulator of mRNA turnover when localized to SGs during the ISR. The association of ZBP1 with target mRNAs in SGs is not essential for mRNA-targeting to these cytoplasmic foci. However, ZBP1 knock-down induced a selective destabilization of target mRNAs during the ISR, while forced expression increased mRNA stability. With the projects proposed, we aim to identify the molecular networks via which ZBP1 and other RNA-binding proteins localized to SGs facilitate the regulation of mRNA fate during the ISR. The identification of these will set the stage to characterize how RNA-metabolism is controlled by RNA-binding proteins during cellular stress.