Research Grants 14/00150-5 - Transdução de sinais, Autofagia - BV FAPESP
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Dissecting the role of Ambra1 in the regulation of calcium metabolism in cells undergoing autophagy

Abstract

The process of autophagy culminates at the maturation step in which the nascent autophagosome fuses with the endosomal/lysosomal system to create a degradative compartment, the autolysosome. Functional lysosomes are critical for the maturation of autophagosomes and for the degradation of their content. The inhibition of autophagosome fusion can thus be detected as accumulation of autophagosomes in the cytoplasm. In contrast with the formation process, the factors regulating Recently, it was found that UVRAG, which is a Beclin-1 binding protein, colocalizes with Rab9-positive endosomes and interacts with the core class C Vps complex containing the proteins Vps11, Vps16, Vps18 and Vps 33. Overexpression of UVRAG promotes autophagosome-lysosome fusion; therefore, it is possible that Beclin-1 is a facilitator of the fusion process in addition to its role in autophagosome formation.We have evidences that Ambra1 localizes to different subcellular compartments, such as cytoskeleton, endoplasmic reticulum and mitochondria, and its activity is regulated by the interaction with different factors depending on its localization. Recently, we identified Spinster1, an intrinsic protein localized on lysosomes, as an Ambra1 interacting protein. It important to mention that Spinster it has been shown as a protein interacting with both Bcl-2 and Beclin1 two members of the Ambra1 functional complexes. Prompted by this finding the aim of this project is to characterize the Ambra1 protein complexes associated with lysosomes, in order to fully elucidate how Ambra1 activity is regulated at these site and whether and how specific stimuli may induce autophagy by activating the specific Ambra1 complexes localized at the lysosomal level. In particular, we want to elucidate whether Ambra1 is involved in the regulation of TPC-dependent release of calcium regulating autophagy. In order to better understand the role of Ambra1 in the regulation of the autophagic process at the lysosomal level, we will analyze the Ambra1 protein network at lysosomal level starting from an in vitro cellular approach, followed by a study in cellular and animal models reproducing neurodegenerative diseases. To this aim, the project will be organized in the following tasks:1. To characterize Ambra1 protein complexes localized on the lysosomal membrane.2. To study the role of Ambra1 in calcium metabolism.3. To evaluate the relevance of Ambra1-interacting proteins in the progression of neurodegenerative diseases in model systems. (AU)

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