Cargo-responsive mechanisms in autophagy

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Project Summary/Abstract The removal of toxic or unwanted cellular structures – such as protein aggregates, intracellular pathogens and damaged organelles – presents a fundamental challenge for eukaryotic cells. To eliminate these structures, which are too large and too complex for the proteasome, cells require an alternative degradation pathway, autophagy. The predominant view in the field is that all autophagy targets are degraded by a common mechanism. However, this understanding comes primarily from studies of only a few model substrates, with the unsubstantiated assumption that other cargoes behave similarly. To test this model, I developed a panel of cargo-specific autophagy reporters amenable to genetic screening, quantitative microscopy, and biochemical manipulation. By this approach, I discovered that autophagy cargo (and their receptors) are instructive for autophagy, such that different cargoes can induce autophagy via different mechanisms. In the process, I discovered a new cohort of proteins that facilitate cargo selection and autophagosome initiation. Going forward, the broad goal of our work is to apply our receptor-centric paradigm to reveal new autophagy mechanisms, dissect the physiological impact(s) of autophagy, and elucidate heretofore unknown lysosomal trafficking pathways. We expect our studies to reshape the traditional view of how autophagy factors function into a more complex web of overlapping mechanisms that ensure robust cytoplasm-to-lysosome delivery. In doing so, we will reveal conserved principles of autophagy and inform our understanding of autophagy dysregulation in disease.