Friday, April 26, 2024
4/26/2024
Project Summary/Abstract: The mTORC1 kinase complex is a major regulator of cell growth and metabolism, and is deregulated in a variety of common human diseases such as diabetes and cancer. In addition, chronic mTOR inhibition increases lifespan in a variety of model organisms. Many of these disease phenotypes have been attributed to the role of autophagy downstream of starvation-induced mTORC1 inhibition. Therefore, understanding the regulation of autophagy by mTORC1 is of great importance to guide future therapeutics and to uncover fundamental cellular biological processes. Of particular interest to us is the role of autophagy-mediated degradation of ribosomes in response to nutrient depravation or mTOR inhibition. We reasoned that because ribosomes make up ~50% and ~80% of the total cellular protein and RNA, that their degradation is likely important for maintaining cellular homeostasis under starvation conditions. This process of ribosome degradation via autophagy (ribophagy) is yet to be fully understood. We recently discovered that NUFIP1, a protein whose nuclear function is associated with snoRNP mediated modification of the ribosome, can act as a selective autophagy receptor for ribosomes in the cytoplasm. NUFIP1-dependent selective autophagy operates downstream of the mTORC1 pathway and is induced via nutrient deprivation or with mTOR inhibitors. The goal of the proposed research is to define the mechanism by which NUFIP1 recognizes ribosomes for degradation, and how mTORC1 is involved in mediating this signal. To that end we propose the following aims: 1. Determine the binding site of NUFIP1 on the ribosome. 2. Identify the modification or accessory protein needed for the starvation regulated NUFIP1-ribosome interaction. 3. Determine how mTORC1 signaling initiates selective ribophagy. By taking both hypothesis driven and unbiased approaches, the proposed work will define the mechanism of selective ribophagy in response to starvation. Determining the NUFIP1-ribosome binding site as well as proteins involved in marking ribosomes for degradation may lead to novel therapies targeting ribosome recycling. This could have implications for diseases like cancer that co-opt autophagy to maintain their proliferative potential.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
