Regulation of the ER-associated Degradation by Importin Beta

知识价值。内质网（ER）是一个大的膜结合囊，用于生产细胞中的许多蛋白质。然而，很大一部分蛋白质在生产过程中或由于致病性损伤（如暴露于有毒物质或基因突变）而出现缺陷。为了解决这个问题，细胞进化出了内质网蛋白质量控制系统来识别那些有缺陷的蛋白质，并将它们从内质网中提取出来进行破坏。当质量控制过程不能正常工作时，有缺陷的蛋白质就会在内质网中积聚，严重时可能导致细胞损伤甚至死亡。因此，有缺陷的蛋白质如何从内质网中移除是一个基本的生物学问题，但不幸的是，人们对这一问题知之甚少。本项目将研究在本实验室发现的输入β蛋白与内质网蛋白质量控制系统中的一组其他蛋白之间意想不到的物理和功能相互作用。众所周知，进口蛋白在细胞核内外运输蛋白质方面具有重要作用。该研究将确定β蛋白在内质网蛋白质量控制中的新作用，从而为这一重要过程的整体调控提供新的见解。更广泛的影响。本项目涉及高中生、高中理科教师、博士后1人、博士生1人。参与这项研究的学员将学习一种综合的方法，利用跨学科的方法，包括分子生物学、生物化学和细胞生物学，来研究进口蛋白Ò的新型内质网蛋白质量控制功能。为促进学员取得较高的科学成就，将编制一份调查问卷，评估他们所学的基本知识和技能。这些信息还将有助于确定培训中的关键需求，这些需求将被纳入实验室未来受训者的指导计划。该项目将利用与当地高中科学项目建立的伙伴关系，扩大代表性不足的学员的参与。参与该项目的科学教师将帮助招募参与该项目的学生，并通过这些经历激励他们班上的其他学生。将制定计划，促进与其他机构实验室的合作，分享研究成果和资源，并加强外联和培训机会。将通过鼓励受训者在科学会议上介绍他们的工作和通过互联网分发电子教育材料来广泛传播这项研究。

Intellectual merit. The endoplasmic reticulum (ER) is a large membrane-bound sac for the production of many proteins in cells. However, a significant fraction of the proteins become defective during production or due to pathogenic insults, such as exposure to toxic agents or genetic mutations. To deal with this problem, cells have evolved an ER protein quality control system to recognize those defective proteins and extract them from the ER for destruction. When the quality control process does not function properly, defective proteins build up in the ER, which in severe cases can lead to cell damage and even cell death. Therefore, how defective proteins are removed from the ER is a fundamental biological problem, but unfortunately remains poorly understood. This project will investigate an unexpected physical and functional interaction, discovered in this laboratory, between importin beta and a group of other proteins in the ER protein quality control system. Importin beta is well known for its function in transporting proteins in and out of the nucleus. The research will establish a new role for importin beta in ER protein quality control and thus will provide new insights into the overall regulation of this important process.Broader impacts. This project will involve high school students, high school science teachers, a postdoctoral fellow, and a PhD student. Trainees involved in this research will learn an integrative approach to the novel ER protein quality control function of importin Ò using interdisciplinary approaches, which will include molecular biology, biochemistry, and cell biology. To foster high scientific achievement of trainees, a questionnaire will be developed to assess the basic knowledge and skills they learn. This information will also help to identify critical needs in training that will be incorporated into the mentoring plans for future trainees in the laboratory. The program will utilize established partnerships with local high school science programs to broaden the participation of underrepresented trainees. Science teachers involved in this project will help to recruit students for this project and through these experiences will inspire other students in their classes. Plans will be undertaken to foster collaborations with laboratories at other institutions to share research results and resources and to enhance outreach and training opportunities. Broad dissemination of this research will be achieved by encouraging trainees to present their work at scientific conferences and by distributing electronic educational materials through the Internet.