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

EAGER：阐明伪磷酸酶 MK-STYX 作为应激反应途径中 mRNA 稳定性调节剂的机制

• 批准号: 1113167
• 负责人: Shanta Hinton
• 金额: $ 30万
• 依托单位: College of William and Mary
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1113167&HistoricalAwards=false
• 关键词: EAGER; Elucidating; Mechanism; Pseudophosphatase; MK

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.

当细胞暴露在高温或太阳紫外线等压力下时，它们会迅速做出反应以确保生存。最快速的反应之一是停止蛋白质的产生，这使细胞能够适应压力。细胞通过隔离信使rna来维持这种控制，信使rna为蛋白质合成提供了蓝图，并将其隔离到称为应激颗粒的特殊隔间中。一种名为G3BP-1的信使RNA结合蛋白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。虽然在过去的八年中对应力颗粒进行了广泛的研究，但大多数研究都集中在G3BP-1和其他参与调节应力颗粒组装的成分上。本研究探讨了MK-STYX在分解应力颗粒和阻断其形成中的新作用。这项研究将深入了解MK-STYX在应激反应中的作用，作为信使RNA稳定性的调节剂和应激颗粒形成的动力学。以下具体目标将被解决：(1)确定MK-STYX对负责蛋白质生产的细胞途径的影响。MK-STYX是否间接激活或绕过这一途径来阻断应力颗粒的组装？MK-STYX是否能稳定蛋白质的产生，从而防止应力颗粒的形成，或者是否需要它来分解它们？(2)确定MK-STYX对应力颗粒组装所需的G3BP-1复合物的影响。MK-STYX是否会破坏G3BP-1和其他支架蛋白之间的相互作用，而这是应力颗粒组装所必需的？(3)确定MK-STYX对应力颗粒动力学所需的细胞骨架和伴侣蛋白的影响。MK-STYX是否与分解所需的热休克蛋白（如Hsp70）相互作用？更广泛的影响。这个项目提供了将研究和教育无缝结合的机会。这将使研究人员能够加强威廉玛丽学院的生物学课程，并为未被充分代表的学生树立积极的榜样。研究者的目标之一是设计生物化学的讲座和实验课程，使学生接触到蛋白质-蛋白质相互作用及其功能的研究。她的研究目标和结果将被纳入她的教学。研究者一直致力于提高未被充分代表的群体参与科学的项目。然而，她已经意识到，仅仅成为一名教员是不足以让非裔美国人和其他少数族裔留在科学领域的。必须鼓励来自代表性不足的群体的个人获得博士学位，成为独立的研究人员。该研究员还将参加一个由hhmi资助的项目，该项目为代表性不足的群体提供独特的本科研究经验，并促进与当地历史上为黑人服务的机构（如汉普顿大学、诺福克州立大学和弗吉尼亚州立大学）的合作，以促进教师和学生之间的专业发展和指导关系。研究者将继续为她的学生提供真正的研究机会，使他们能够参与到令人兴奋的科学发现过程中来。