The Roles of the Dynamin-Related Protein Vps1 and the ESCRT Complex in Microautophagy

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Microautophagy is a poorly-characterized autophagic pathway defined by direct invagination of vacuolar (fungi) or lysosomal (higher eukaryotes) membrane for engulfment and degradation of organelles and cytosolic components. Microautophagy is required for cell survival under conditions of stress, such as nutrient limitation, and for resumption of cell growth on recovery from stress. Strikingly, microautophagy is also a key regulator of TOR signaling, which plays well-established roles in growth, survival and lifespan control. The molecular mechanism of microautophagy and how it regulates TOR signaling is not understood. Our long-term goal is to understand the mechanism of microautophagy and how microautophagy is harnessed to regulate signaling cascades required for growth and development. Our preliminary data demonstrates that the membrane remodeling required for microautophagy depends on the dynamin-related protein (DRP) Vps1 and the ESCRTIII component Snf7. DRPs and ESCRTs are fascinating membrane remodeling machines that are vital for several fundamental cellular processes including membrane trafficking, mitochondrial dynamics, cytokinesis and viral budding. DRPs and ESCRTs both couple membrane deformation to self-assembly. Deficiencies in DRPs and ESCRTs are associated with numerous pathologies due to their central roles in homeostasis, including neurodegenerative disorders. Our central hypothesis is that the functional interaction between DRPs and ESCRTs forms the molecular basis for membrane invagination in microautophagy. Furthermore, we propose that nutrient and stress signaling pathways converge on Vps1 and ESCRT to regulate their novel function in microautophagy to, ultimately, control TOR signaling and cell growth. Using genetic, proteomic, cytological and structural approaches, we will characterize the mechanism of recruitment of DRP and ESCRT to sites of microautophagy, as well as the regulatory determinants of their function in TOR signaling. Completion of this work will provide an in-depth understanding of the machinery required for microautophagy. It will shed mechanistic light on novel aspects of DRP and ESCRT function that may have broad implications for membrane remodeling processes in general. Finally, this work will provide important insight into the mechanisms whereby microautophagy regulates TOR signaling. Dysregulation of TOR signaling is associated with several human cancers. Hence, the machinery of microautophagy, as a regulator of TOR signaling, represents a novel target for development of anticancer and antifungal drugs.