RRAG GTPases link nutrient availability to gene expression, autophagy and lysosomal biogenesis

Abstract

When the levels of intracellular amino acids are high, RRAG GTPases recruit MTORC1 to lysosomes and promote its activation. We found that RRAGs also recruit specific MTORC1 substrates to the lysosomal surface, thus facilitating MTORC1-mediated phosphorylation and regulation. In particular, active RRAGs interact with the transcription factor EB (TFEB), the master regulator of a gene network that promotes lysosomal biogenesis and autophagy. Redistribution to lysosomes is critical for MTORC1-dependent inactivation of TFEB under nutrient-rich conditions. Therefore, RRAGs play a critical role coordinating nutrient availability and cellular clearance.

Keywords: MITF; MTORC1; RRAG; TFEB; autophagy; lysosomes.

Figure 1. Model of the mechanism of TFEB regulation by RRAG GTPases. In nutrient-rich conditions, active RRAGs promote recruitment of MTORC1 and TFEB to the lysosomal membrane. Active MTORC1 phosphorylates TFEB in several residues including S211. Phosphorylation of TFEB at S211 creates a binding site for YWHA (14-3-3). We propose that YWHA may mask the RRAG-binding domain in TFEB (represented in yellow) and subsequently sequester TFEB in the cytosol. Under starvation conditions, RRAG GTPases and MTORC1 are inactivated and TFEB can no longer redistribute to lysosomes. Consequently, the TFEB-YWHA complex dissociates, thus allowing transport of TFEB to the nucleus where it mediates the activation of a transcriptional network that promotes autophagy, lysosomal biogenesis and increased lysosomal degradation. In summary, TFEB localization and regulation are nutrient dependent. In fully fed cells TFEB continuously shuttles between the cytosol and lysosomes, whereas under nutrient-deprivation conditions, TFEB is transported from the cytosol to the nucleus.