Grant: Discovery Grants Program - Individual

Summary of Proposal Autophagy is a well-conserved intracellular recycling mechanism that helps cells maintain organelle and protein homeostasis (proteostasis) under various stresses. Autophagy consists of the sequestration of intracellular material into a vesicle called an autophagaosome where it is transported to the lysosome for degradation. Different organelles in the cytoplasm can be specifically targeted for autophagy via selective autophagy engaging autophagy receptors. The major selective autophagy receptor SQST-1/SQSTM1 (also named p62) is able to recognize ubiquitinated cargos and different organelles and direct their sequestration into autophagosomes. Anchored at the autophagosome, small ubiquitin-like proteins of the ATG8 family of proteins, including LGG-1/GABARAP, interact with autophagy receptors like SQST-1/SQSTM1 to facilitate selective autophagy. How cells regulate these interactions and cargo selection during selective autophagy is not fully understood. This proposal seeks to decipher the interacting network associated with SQST-1/SQSTM1 and LGG-1/GABARAP, and study new autophagy regulators in order to better understand how cells modulate selective autophagy to improve stress resistance and proteostasis. Using the powerful system of the nematode C. elegans, we will use a combination of Cell Biology, Genetics and Biochemistry to elucidate how selective autophagy mediated by SQST-1 and LGG-1 is regulated. We hypothesize that SQST-1 and LGG-1 may interact readily with organelles that are subjected to proteostatic stress and with partners that mediate autophagy. Our preliminary data suggest that the mitochondria is preferentially subjected to SQST-1-mediated selected autophagy, while LGG-1 interacts with a wider array of proteins and preferred cargos. Here, we will determine the role of interacting proteins to find key regulators of selective autophagy and overall proteostasis. Our proposal also includes the development of new quantitative tools necessary to properly study mitophagy, the selective autophagy of mitochondria, in C. elegans. Our approach will also study the emerging role of subcellular autophagy protein partitioning in selective autophagy and proteostasis. Altogether, this study will provide important knowledge on the regulatory network associated with selective autophagy.