Postdoctoral Trainee, Department of Cel;l and Developmental Biology
1161 21st Avenue South, Medical Center North, Nashville, TN, TN 37232
Sora Lee, Ph.D., joined the program in 2015 under the mentorship of Jason MacGurn, PhD, and her research focuses on re-wiring protein degradation networks to target inflammation. There is mounting evidence that many human diseases – particularly diseases related to protein misfolding and aggregation such as neurodegenarative disorders – are associated with diminished function of the ubiquitin-proteasome system and altered ubiquitin homeostasis. Given the emerging consensus that dysregulation of ubiquitin homeostasis is a key feature of neurodegeneration, some have proposed restoring ubiquitin levels as a potential therapeutic strategy. However, very little is known about regulation of ubiquitin homeostasis in physiological conditions, during cellular aging, in response to cellular stress, or in states of disease. Thus, there is a critical need to dissect the basic mechanisms responsible for regulating ubiquitin metabolism and to identify new pathways which may be targeted to facilitate precise manipulation of ubiquitin homeostasis in the context of disease cells. In MacGurn lab, Dr. Lee found that phosphorylation of ubiquitin regulates its metabolism in the cells. Based on the preliminary results from live cell imaging, reconstitution biochemistry, and biophysical experiments, it is proposed that direct phosphorylation of ubiquitin prevents the recycling of ubiquitin conjugates from substrates during degradation, and that the cellular concentration of ubiquitin is tightly regulated by a ubiquitin phosphoregulatory cycle. These findings have important implications for how cells maintain ubiquitin homeostasis and may reveal therapeutic strategies for restoring ubiquitin levels in the context of disease.