GENETICS OF ENDOCYTIC TRAFFICKING IN THE DROSOPHILA EYE

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Neurons in adults are essentially irreplaceable and especially vulnerable to the accumulation of protein aggregates, dysfunctional mitochondria, and similarly distractive agents. The most important pathway available to neurons to limit such damage is autophagy. This pathway, initially described in the context of the mTor-regulated starvation-induced metabolic rescue pathway in yeast and mammalian cells, is initiated by the formation of an isolation membrane followed by its expansion, the engulfment of cytoplasmic content into a closed autophagosome and its fusion to the lysosomes and degradation of autophagosomal content. Beyond its importance in the starvation response, starvation and mTor-independent autophagy is increasingly recognized as an important quality control mechanism that reduces degeneration of neurons and photoreceptor cells and has implications for cancer and infectious diseases. Therefore, the distinct cellular signaling pathways that adjust the rate of autophagy to the cell’s physiology are important to understand. Because excessive autophagy is lethal to cells, the different signaling pathways inducing autophagy must be careful coordinated and calibrated. For one such pathway, the Acinus protein is as a critical regulator. The Acinus protein integrates signals from multiple pathways to modulate the function of core autophagy proteins and stimulate the induction of starvation-independent autophagy. This grant aims to understand the molecular mechanisms that regulate the levels of Acn protein and its activity. For this purpose, in Aim 1, we propose to define upstream regulators of Acinus including the phosphatases and kinases responsible for regulating its activity and explore their potential as possible drug targets. In Aim 2, we will analyze the mechanistic link between Acinus and its effector Atg1, the master regulatory kinase of the autophagy pathway. In Aim 3, we will explore physiological consequences of disrupting the Acn-Atg1 signaling module in the context of visual system.