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 Ã’ 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.