MTOR, PIK3C3, and autophagy: Signaling the beginning from the end

Abstract

A key point in starvation-induced autophagy occurs at the end of the process, where lysosomes are regenerated from autolysosomes through a pathway termed autophagic lysosome reformation (ALR). ALR occurs when autolysosomal MTOR becomes reactivated by amino acids derived from the autophagic delivery of protein cargo. This activation not only turns off autophagosome formation but also leads to reformation of lysosomes, ready for the next round of autophagy, through a series of events involving autolysosomal tubulation. We have now found that MTOR regulates multiple steps of ALR including direct activation of the PIK3C3-UVRAG lipid kinase complex to enable autolysosomal tubules to break away and regenerate lysosomes.

Keywords: MTOR; UVRAG; VPS34; autophagic lysosome reformation; lysosome; phosphatidylinositol 3-phosphate; tubulation.

Figure 1.

The autolysosome plays a central role as a signaling platform for the resolution of autophagic responses. Following fusion of an autophagosome with the lysosome, the autolysosome is generated and degrades cellular material. The release of newly acquired nutrients from the autolysosome locally activates MTOR at the lysosome and is critical for a 2-part response. First, the activation of MTOR can inhibit the autophagy initiation machinery to prevent further autophagosome formation. Second, MTOR activity drives autolysosome tubulation and phosphorylates the PIK3C3-UVRAG complex to generate localized PtdIns3P required for the subsequent scission of tubules. The cleaved tubules or proto-lysosomes are then able to mature by acquisition of hydrolases into new lysosomes primed for further fusion.