Regulation of selenium metabolism and stress response

PROJECT SUMMARY / ABSTRACT Selenium is a trace element co-translationally incorporated as the 21st amino acid selenocysteine into selenoproteins. Due to the unique properties of selenium, many selenoproteins have been implicated in maintaining the reduction-oxidation homeostasis. The glutathione-dependent peroxidase GPX4 reduces lipid peroxide into non-toxic lipid alcohol. It provides one of the primary cellular mechanisms to prevent ferroptosis, a regulated cell death caused by the excessive accumulation of oxidatively damaged lipids. Using synthetic lethal screens, we and others have recently discovered the low-density lipoprotein receptor-related protein LRP8 impacts cell sensitivity to ferroptosis by maintaining selenium levels. The decrease in cellular selenium leads to ribosome collision, a premature termination of selenoprotein translation, and systematic changes in transcriptome and proteome, indicating the importance of this essential micronutrition in maintaining cell functions and viability. Yet, how selenium metabolism is regulated and how cells deal with low selenium remain incompletely understood. This is mainly due to a lack of tools to consistently and efficiently deplete cellular selenium, as removing selenium from cell culture supplements is complicated and expensive. To overcome this critical gap in knowledge, we create a low selenium cell system with a 60% decrease in total selenium levels, which mimics the effect of a selenium deficiency diet that causes several diseases in humans. In the next five years, taking advantage of this cell system, we will investigate mechanisms underlying the regulation of selenium metabolism and address two fundamental questions: 1. How does the regulation of selenium impact cell viability? 2. How do cells respond to low levels of selenium? Our research will not only advance our understanding of selenium function and mechanisms governing cell response to stress but also will provide the basis for developing new therapeutic tools to treat diseases associated with the dysregulation of selenium and its metabolism. The techniques and experience acquired in this project will prepare our group for future research exploring the molecular machinery of selenium-mediated maintenance of cellular homeostasis.