EAGER: Elucidating the Mechanism of Pseudophosphatase MK-STYX as a Regulator of mRNA Stability in the Stress Response Pathway

当细胞暴露在高温或来自太阳的紫外线等压力下时，它们会迅速做出反应，以确保生存。最快的反应之一是停止蛋白质生产，这使细胞能够适应压力。细胞通过将信使RNA隔离到称为压力颗粒的特殊隔间来维持这种控制，信使RNA为蛋白质合成提供了蓝图。信使RNA结合蛋白G3BP-1被广泛认为是应激颗粒的重要组成部分。研究人员最近报道，另一种名为MK-Styx的蛋白质与G3BP-1相互作用，抑制应激颗粒的形成。尽管应激颗粒在过去八年中得到了广泛的研究，但大多数研究仅集中在G3BP-1和其他参与调节应激颗粒组装的成分上。这项研究探索了MK-Styx在分解应力颗粒和阻止其形成方面所起的新作用。这项研究将深入了解MK-Styx作为信使RNA稳定性的调节器在应激反应中所起的作用，以及在应激颗粒形成的动力学中的作用。具体目标如下：(1)确定MK-Styx在负责蛋白质生产的细胞途径中的作用。MK-Styx是否间接激活或绕过这一途径来阻断应激颗粒组装？MK-Styx是稳定蛋白质的产生，防止应激颗粒的形成，还是其分解所必需的？(2)确定MK-Styx对应激颗粒组装所需的G3BP-1复合体的影响。MK-Styx是否干扰G3BP-1与应激颗粒组装所需的其他支架蛋白之间的相互作用？(3)确定MK-Styx对应激颗粒动力学所需的细胞骨架和伴侣蛋白的影响。MK-Styx是否与拆解所需的热休克蛋白相互作用，如Hsp70？更广泛的影响。该项目提供了将研究和教育无缝结合的机会。它将使研究人员能够加强威廉和玛丽学院的生物课程，并为代表不足的学生树立积极的榜样。研究人员的目标之一是设计一门生物化学的讲座和实验室课程，让学生了解蛋白质-蛋白质相互作用及其功能的研究。她的研究目标和成果将融入到她的教学中。这位研究人员一直致力于促进未被充分代表的群体参与科学的项目。然而，她已经意识到，仅仅是一名教职员工并不足以留住科学领域的非裔美国人和其他少数族裔。当务之急是鼓励来自代表性不足群体的个人获得博士学位，自己成为独立调查人员。这位调查员还将参加HHMI资助的一个项目，该项目为代表不足的群体提供独特的本科生研究体验，并促进与汉普顿大学、诺福克州立大学和弗吉尼亚州立大学等当地历史上为黑人服务的机构的合作，以促进专业发展和师生之间的指导关系。这位研究人员将继续为她的学生提供真正的研究机会，让他们可以参与到令人兴奋的科学发现过程中。

When cells are exposed to stress such as high temperature or ultraviolet rays from the sun, they respond quickly to ensure survival. One of the most rapid responses is stopping protein production, which allows cells to adapt to stress. Cells maintain this control by sequestering messenger RNAs, which provide the blueprint for protein synthesis, to special compartments called stress granules. A messenger RNA binding protein named G3BP-1 is widely accepted as an important component of stress granules. Researchers recently reported that another protein called MK-STYX interacts with G3BP-1 and inhibits stress granule formation. Although stress granules have been studied extensively for the past eight years, most studies have focused exclusively on G3BP-1 and other components involved in regulating stress granule assembly. This research explores the novel role MK-STYX has in disassembly of stress granules and in blocking their formation. This study will provide insight into the role MK-STYX plays in the stress response, as a regulator of messenger RNA stability and in the dynamics of stress granule formation. The following specific aims will be addressed: (1) Determine the effect of MK-STYX on the cellular pathway responsible for protein production. Does MK-STYX indirectly activate or bypass this pathway to block stress granule assembly? Does MK-STYX stabilize protein production, which would prevent stress granule formation, or is it required for their disassembly? (2) Determine the effect of MK-STYX on the G3BP-1 complex required for stress granule assembly. Does MK-STYX disrupt interactions between G3BP-1 and other scaffold proteins, which are required for stress granule assembly? (3) Determine the effect of MK-STYX on the cell cytoskeleton and chaperones required for stress granule dynamics. Does MK-STYX interact with heat shock proteins required for disassembly, such as Hsp70?Broader Impacts. This project provides the opportunity to integrate seamlessly research and education. It will allow the investigator to enhance the biology curriculum at the College of William & Mary and to serve as a positive role model for underrepresented students. One of the investigator's goals is to design a lecture and laboratory course in biological chemistry, which will expose students to the study of protein-protein interactions and their function. Aims and results of her research will be incorporated into her teaching. The investigator has always been committed to programs that enhance participation of underrepresented groups in science. However, she has realized that just being a faculty member is not enough to retain African-Americans and other minorities in the sciences. It is imperative to encourage individuals from underrepresented groups to obtain PhDs become independent investigators themselves. The investigator will also participate in an HHMI-funded program that provides underrepresented groups with a unique undergraduate research experience and that and promotes collaborations with local historically black-serving institutions such as Hampton University, Norfolk State University, and Virginia State University to foster professional development and mentoring relationships between faculty and students. The investigator will continue to provide real research opportunities for her students so that they may engage in the exciting process of scientific discovery.