Gαq is a novel modulator of autophagy

Résumé

The highly conserved autophagy processes play a central role in cellular homeostasis by allowing the lysosomal degradation of cellular components either in basal conditions or in response to fluctuations in the internal or external microenvironment, thus helping to adapt to different stress situations. Autophagy is regulated in a cell-autonomous fashion mainly through AMP-activated protein kinase (AMPK) and mammalian target or rapamycin complex 1 (mTORC1) modulators. Recent studies suggest that nutrients may also modulate autophagy in a systemic manner through different nutrient-sensing receptors, and emerging evidence suggest that members of the G protein-coupled receptors (GPCRs) membrane receptor family could play such a role. These GPCR nutrient receptors act via different G proteins, including Gαq/11. In this work, we unveil an unanticipated role of Gαq/11 as a key component of the cellular nutrient-sensing machinery. Cells lacking Gαq/11 display higher basal autophagy and an earlier and prolonged induction of this process upon serum removal or in the absence of amino acids or glucose, suggesting that Gαq/11 acts as a general sensor of nutrient availability. Moreover, we describe the presence of Gαq in lysosomal and autophagic compartments and a dynamic redistribution of Gαq between autophagic vacuoles upon nutrient deprivation. However, Gαq is not a substrate of autophagy under nutrient stress conditions, consistent with a role as an autophagy modulator. Importantly, we demonstrate that Gαq affects autophagy processes via the modulation of the key mTORC1 signaling hub, and identify p62/SQSTM1 as the effector linking Gαq/11 to the activation of mTORC1 via the formation of Gαq/p62/mTORC1 multi-molecular complexes. We find that p62 displays most of the features of a bona fide Gαq effector and that these proteins associate through a PB1-like interaction, involving the PB1 domain of p62 and the acidic PB1-binding region of Gαq. The dynamic formation of Gαq/p62 complexes in the presence of nutrients contributes to the activation of mTORC1, thus allowing the subsequent inactivation of macroautophagy in these metabolic conditions. Interestingly, we show that Gαq/11 is also required for the proper lysosomal positioning upon nutrient starvation or recovery, suggesting a role for Gαq/11 in the coordination of mTORC1 activation and lysosomal trafficking processes. On the other hand, Gαq localizes in lysosomes enriched in chaperone-mediated autophagy (CMA) and appears to positively modulate this process in both basal and prolonged starvation conditions. Our results postulate Gαq as a central molecular switch between different autophagic pathways, thus helping to maintain cellular homeostasis upon nutrient fluctuations.