Atg1 as the master regulator of autophagosome completion

Samenvatting

Autophagy is a conserved intracellular degradative pathway that plays a key role in many physiological processes and numerous pathologies including cancer, neurodegeneration and muscular dystrophies. The key actors of this process are the autophagy-related (Atg) proteins. Upon autophagy induction, the Atg1 kinase complex is activated and phosphorylates several Atg proteins initiating the formation of the double-membrane autophagosomes, which sequester the structures targeted to destruction. Once an autophagosome is completed, its fusion with lysosomes and subsequent cargo degradation are preceded by the dissociation of most Atg proteins, a step essential for the normal progression of autophagy. The molecular bases underlying this step, however, remain unknown.

The goal of this project is to unravel the mechanisms leading to the dissociation of Atg proteins from complete autophagosomes. Current evidences suggest that inactivation of the Atg1 kinase complex and concomitant activation of an antagonizing phosphatase provokes the disassembly of the Atg machinery. To test this hypothesis, we will combine yeast genetics with biochemical and proteomics approaches to identify Atg1 substrates within the Atg machinery and generate corresponding phospho-mimicking and non-phosphorylable mutants to study their role during autophagosome completion. We will also perform a screen to identify the phosphatases counteracting Atg1 and investigate their regulation. Finally, we will study possible signals that could lead to the inhibition of Atg1 kinase activity upon autophagosome completion.

Altogether, our results will allow deciphering a step of autophagy that so far has only marginally studied. Importantly, some of the mechanisms clarified at the molecular level could become targets for autophagy-based therapies.

Kenmerken

Projectnummer

ALWOP.310

Hoofdaanvrager

Prof. dr. F. Reggiori

Verbonden aan

Rijksuniversiteit Groningen, Universitair Medisch Centrum Groningen, Celbiologie

Looptijd

01/09/2017 tot 31/08/2020

Budget

€ 284.477