Autophagy is an important cellular response to metabolic stress, challenges to proteostasis and diverse other insults such as infections. These conditions induce the formation of an isolation membrane that initiates the engulfment of unspecific cytoplasmic content in the context of the starvation. In response to other stressors more specific targets may be tagged for degradation such as aggregates of misfolded proteins, dysfunctional mitochondria, or pathogens. The initial isolation membranes (also called phagophores) grow and eventually engulf the cargo in double-membraned autophagosomes. Their subsequent fusion with late endosomes and lysosomes will deliver the autophagosomal content for degradation and recycling of nutrients to stressed cells. Beyond its importance in the starvation response, basal 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, it is important to understand the distinct cellular signaling pathways that adjust the rate of autophagy to a cell?s physiology. Careful calibration of such signaling is essential as excessive autophagy is lethal to cells. We identified Acinus as a regulator in the induction of basal, starvation-independent autophagy. The Acinus protein integrates signals from multiple pathways to modulate the function of core autophagy proteins. This grant aims to understand the molecular mechanisms that regulate the levels of Acn protein and its activity.
Aim 1 proposes to define the phosphatases and kinases responsible for regulating its activity.
Aim 2 will analyze the mechanistic link between Acinus and the activation of Atg1, the master regulatory kinase of the autophagy pathway.
Project(Narrative( ! Autophagy is an important cell biological mechanism that cells use to restore energy supplies at time of starvation and to rid themselves of damaging content such as aggregated proteins during neurodegeneration, dysfunctional mitochondria or invading bacteria. The specific aims described in this proposal will explore the mechanism boosting starvation-independent autophagy to address cellular challenges without the damage that can result from excessive autophagy. Because autophagy is important for suppressing the early effects of neurodegeneration and has complicated and sometimes contradictory consequences in the context of different cancers, understanding these mechanisms is important for human health.!
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