Saturday, November 23, 2024
11/23/2024
Autophagy is a cellular process in which cytosolic material is captured in double-membrane vesicles, termed autophagosomes. Subsequently, autophagosomes fuse with the vacuole, in yeast, or lysosomes, in mammalian cells, leading to the degradation of the captured contents. Autophagy can capture a diversity of cytosolic cargos, including organelles, large protein aggregates and intracellular pathogens. As such, autophagy plays critical roles in maintaining organelle quality, preventing the accumulation of protein aggregates and clearing intracellular pathogens. Therefore, defects in autophagy have been associated with various human diseases, including cancer, neurodegenerative disease and inflammatory disease. During autophagy, cargo can be captured via a non-selective or selective mechanism. In selective autophagy, cargos are identified by selective autophagy receptors (SARs). SARs are either soluble cytosolic proteins recruited to the cargo upon autophagy initiation or integral membrane proteins embedded in the organelle membrane that will become a cargo for selective autophagy. While the mechanisms by which cytosolic SARs initiate selective autophagy have become increasingly clear, the mechanisms by which integral membrane SARs coordinate with the autophagy machinery to initiate selective autophagy are still not well understood. The proposed work will use mitochondrial autophagy (mitophagy) in yeast as a model system to investigate the mechanisms by which integral membrane SARs coordinate with the autophagy machinery to initiate selective autophagy. Mitophagy in yeast is an ideal system to study selective autophagy initiation as yeast have only a single SAR for mitochondria, termed Atg32. In contrast, mammalian cells have five integral membrane SARs for mitochondria making it more challenging to interpret knockdown or mutagenesis studies of any individual SARs as other related SARs may compensate. This proposal will utilize a cross-disciplinary approach combining cell biology, lipid biochemistry, biochemical reconstitution and structural biology to study mitophagy initiation. The proposed work will help develop a molecular understanding of the mechanisms of selective autophagy initiation by integral membrane SARs, provide a starting point for studying other integral membrane SARs using biochemical approaches and provide novel methods for studying these systems.
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).
