Galectins control MTOR and AMPK in response to lysosomal damage to induce autophagy

Abstract

The Ser/Thr protein kinase MTOR (mechanistic target of rapamycin kinase) regulates cellular metabolism and controls macroautophagy/autophagy. Autophagy has both metabolic and quality control functions, including recycling nutrients at times of starvation and removing dysfunctional intracellular organelles. Lysosomal damage is one of the strongest inducers of autophagy, and yet mechanisms of its activation in response to lysosomal membrane damage are not fully understood. Our recent study has uncovered a new signal transduction system based on cytosolic galectins that elicits autophagy by controlling master regulators of metabolism and autophagy, MTOR and AMPK, in response to lysosomal damage. Thus, intracellular galectins are not, as previously thought, passive tags recognizing damage to guide selective autophagy receptors, but control the activation state of AMPK and MTOR in response to endomembrane damage. Abbreviations: MTOR: mechanistic target of rapamycin kinase; AMPK: AMP-activated protein kinase / Protein Kinase AMP-Activated; SLC38A9: Solute Carrier Family 38 Member 9; APEX2: engineered ascorbate peroxidase 2; RRAGA/B: Ras Related GTP Binding A or B; LAMTOR1: Late Endosomal/Lysosomal Adaptor, MAPK and MTOR Activator 1; LGALS8: Lectin, Galactoside-Binding, Soluble, 8 / Galectin 8; LGALS9: Lectin, Galactoside-Binding, Soluble, 9 / Galectin 9; TAK1: TGF-Beta Activated Kinase 1 / Mitogen-Activated Protein Kinase Kinase Kinase 7 (MAP3K7); STK11/LKB1: Serine/Threonine Kinase 11 / Liver Kinase B1; ULK1: Unc-51 Like Autophagy Activating Kinase 1.

Keywords: AMPK; APEX2; MTOR; Rag GTPases; Ragulator; SLC38A9; autophagy; galectin 8; galectin 9; lysosome.

Figure 1.

Model depicting how galectins control MTOR and AMPK. Lysosomal damage causes MTOR inhibition through a system termed GALTOR. LGALS8 recognizes lumenal glycans (depicted as an antennary structure) and inhibits MTOR via interactions with the Ragulator-RRAG-SLC38A9 system. Lysosomal damage activates AMPK through LGALS9 with the engagement of TAK1. Galectins control autophagy, and possibly metabolic reprograming, in response to lysosomal damage via MTOR and AMPK.