The control of mRNA fate during cellular stress

细胞应激期间 mRNA 命运的控制

• 批准号: 56030331
• 负责人: Professor Dr. Stefan Hüttelmaier
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/56030331?language=en
• 关键词: control; mRNA; fate; during; cellular

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.

整合应激反应（ISR）的一个重要组成部分是可逆的翻译抑制。这种mRNA沉默发生在称为应激颗粒（SG）的不同的细胞质病灶中，应激颗粒（SG）与通常用作mRNA衰变中心的加工体（PB）瞬时缔合。如何保护mRNA在SGs中不被降解仍然很难理解。在最近的研究中，我们发现RNA结合Zipcode结合蛋白1（ZBP 1），通常参与调节非应激细胞中特定mRNA的细胞质命运，是ISR期间定位于SG时mRNA周转的关键调节因子。ZBP1与SGs中靶mRNA的结合对于mRNA靶向这些细胞质病灶不是必需的。然而，ZBP1敲低诱导ISR过程中靶mRNA的选择性不稳定，而强制表达增加mRNA的稳定性。随着项目的提出，我们的目标是确定ZBP1和其他RNA结合蛋白定位到SGs的分子网络，促进ISR过程中mRNA命运的调节。这些的鉴定将为表征细胞应激期间RNA结合蛋白如何控制RNA代谢奠定基础。