Mechanisms of autolysosome formation
Lysosomes fuse with autophagosomes to enable the completion of autophagy, a cellular ‘self-eat’ process that is a major contributor to the homeostasis of both normal and cancer cells. However, our understanding of how the lysosomal and autophagic systems interact is still limited. For example, it has been assumed that, once formed, autophagosomes fuse with lysosomes and release their breakdown products non-selectively and in a non-regulated fashion. However, the newly discovered role of the lysosome as a cellular nutrient sensor suggests a different scenario, that the cell’s nutrient status may tightly regulate autophagosome-lysosome fusion and the subsequent release of nutrients from the lysosomal lumen. Testing this hypothesis rigorously within the complex environment of living cells is sure to be challenging. Thus, we will exploit the power of in vitro reconstitution to recapitulate lysosome-autophagosome fusion and dissect the mechanistic requirements of this process. Combining dynamic imaging and unbiased metabolite profiling, our goal is to achieve a detailed understanding of how the lysosome interfaces with other metabolic pathways in the cell.