WDR83/MORG1 inhibits RRAG GTPase-MTORC1 signaling to facilitate basal autophagy

TL;DR

This paper shows how the protein WDR83/MORG1 helps control autophagy by inhibiting the MTORC1 pathway, which is important for cell health and cancer outcomes.

Contribution

The paper identifies WDR83/MORG1 as a novel negative regulator of MTORC1 signaling that enables basal autophagy.

Findings

WDR83 interacts with Ragulator and active RRAG GTPases to block MTORC1 recruitment to lysosomes.

WDR83 depletion increases MTORC1 activity and reduces basal autophagy.

Low WDR83 levels are linked to poor cancer prognosis and increased cell proliferation and migration.

Abstract

Macroautophagy/autophagy is a conserved lysosomal degradation process composed of both selective and nonselective degradation pathways. The latter occurs upon nutrient depletion. Selective autophagy exerts quality control of damaged organelles and macromolecules and is going on also under nutrient-replete conditions. Proper regulation of autophagy is vital for cellular homeostasis and prevention of disease. During nutrient availability, autophagy is inhibited by the MTORC1 signaling pathway. However, selective, basal autophagy occurs continuously. How the MTORC1 pathway is fine-tuned to facilitate basal constitutive autophagy is unclear. Recently, we identified the WD-domain repeat protein WDR83/MORG1 as a negative regulator of MTORC1 signaling allowing basal, selective autophagy. WDR83 interacts with both the Ragulator and active RRAG GTPases to prevent recruitment of the MTORC1 complex to the lysosome. Consequently, WDR83 depletion leads to hyperactivation of the MTORC1 pathway and a strong decrease in basal autophagy. As a consequence of WDR83 depletion cell proliferation and migration increase and low levels of WDR83 mRNA are correlated with poor prognosis for several cancers.

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