Autophagy contributes to cellular homeostasis during times of starvation and is also induced in response to diverse cellular stress situations. These conditions induce the formation of an isolation membrane that initiates the engulfment of unspecific cytoplasmic content, in the context of the starvation response, or specific cargoes tagged for removal such as dysfunctional mitochondria, aggregates of misfolded proteins, or pathogens that escaped into the cytoplasm. Nascent isolation membranes (also called phagophores) continue to grow until their cargo is entirely engulfed in the resulting double-membrane autophagosomes. Their subsequent fusion with late endosomes and lysosomes will trigger the degradation of autophagosomal content and provide new nutrients and energy 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. By contrast, excess autophagy can result in cell death. Therefore it is important to understand the various cellular signaling pathways that adjust the rate of autophagy to the cell's physiology. Acinus is a protein that plays a critical role in this process, as it integrates the signal from multiple pathways to modulate the function of the 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 proteases that cleave Acinus and the kinases that are responsible for regulating its degradation.
Aim 2 will analyze the mechanistic connection between Acinus-induced autophagy and signaling through the Hippo pathway.
Aim 3 will investigate the mechanisms by which spermidine modifies Acinus-induced autophagy.
Autophagy is a basic 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, dysfunctional mitochondria or invading bacteria. Dysfunction of this process results in the degeneration of neurons and photoreceptor cells. The specific aims described in this proposal will explore the regulatory mechanisms by which photoreceptor cells adjust the level of autophagy to address cellular challenges without the damage that results from excessive autophagy. This work is important for human health, because autophagy is important to fight the early effects of neurodegeneration and in the context of cancer.
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