Amount Awarded: $25,000
Autophagy (cellular "self-eating") is a conserved cell stress-response and survival pathway that has attracted enormous interest for its therapeutic potential in aging, cancer, neurodegeneration, and beyond. Single membrane ATG8 conjugation (SMAC) is a newly discovered pathway that is distinct from autophagy but uses overlapping molecular machinery and also functions in stress responses. Deconstructing the roles of autophagy and SMAC has become one of the most exciting frontiers in understanding cellular stress responses. This proposal combines the efforts of a world leader in the structural biology of autophagy-related processes (Hurley) with a world leader in subcellular membrane biology, signaling, and its relationship to disease (Stenmark). The Hurley lab will use cryo-EM to determine the structure of mammalian V-ATPase bound to ATG12-5-16L1. Using the structure as a starting point, this lab will engineer structure-based mutations to probe the role of ATG16L1 in SMAC. The Stenmark lab will use a combination of genome editing and advanced light microscopy to study the functional consequences of the engineered mutations in cellular pathways, including phagocytosis, autophagy and lysosome repair.