Stress responses revealing new modes of RNA-binding protein function

应激反应是保护细胞免受环境伤害的关键生物学过程。基于其中一位申请者的实验室发明和完善的RNA相互作用组捕获技术，我们最近发现了蛋白质SERBP1和PCBP1的多腺化RNA结合的应激反应调节。已知SERBP1与因应激而沉默的核糖体有关。我们还获得了更多的实验结果，表明在应激的早期阶段，SERBP1从与多腺苷化的RNA结合切换到与rRNA的结合，并支持eIF2α的磷酸化。PCBP1是一种已知的RNA结合蛋白和铁伴侣蛋白。虽然这些功能被认为是完全独立的，但我们现在发现，PCBP1的RNA结合受到氧化应激的抑制，从而将PCBP1的RNA结合和铁代谢功能联系在一起。显然，应激反应通过调节的RNA结合将SERBP1和PCBP看似无关的细胞功能联系在一起。这里提出的项目将深入探索这些观察结果，并提供对RNA结合蛋白前所未有的差异功能的机制洞察力。我们的工作将定义受调控的RNA结合如何在应激条件下对细胞反应做出贡献。

Stress responses are key biological processes to protect cells from environmental insults. Based on the RNA-interactome capture technology invented and refined in the laboratory of one of the applicants, we have recently discovered the stress-responsive regulation of polyadenylated RNA-binding of the proteins SERBP1 and PCBP1. SERBP1 is known to associate with ribosomes that are silenced by stress. We have obtained additional experimental results indicating that SERBP1 switches from binding to polyadenylated RNA to binding to rRNA and supports eIF2α phosphorylation during the early phase of stress. PCBP1 is a known RNA-binding protein and a known iron-chaperoning protein. While these functions have been thought to be completely independent of each other, we have now discovered that PCBP1 RNA-binding is inhibited by oxidative stress, thus linking the RNA-binding and iron metabolism functions of PCBP1. Apparently, stress responses connect seemingly unrelated cellular functions of SERBP1 and PCBP by regulated RNA binding. The project proposed here will deeply explore these observations and provide mechanistic insight into unprecedented differential functions of RNA-binding proteins. Our work will define how regulated RNA binding contributes to the cellular responses under conditions of stress.