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.

A risk signature with four autophagy‐related genes for predicting survival of glioblastoma multiforme

“…Our study was identical to the opinion that DIRAS3 was correlated with poor prognosis of GBM and was a risk factor for GBM survival. As a member of lectin family, LGALS8 (galectin‐8) plays key roles in various cellular processes, such as autophagy, cytoskeletal rearrangement, immunity and inflammation, as well as tumour progression . LGALS8 can recognize lysosome damage and promote autophagy through inhibiting mTOR activity .…”

YAP Manipulates Proliferation Via PTEN/AKT/mTOR-mediated Autophagy in Lung Adenocarcinomas

“…4c, d). It is well-known that the degradation of the phospho-mTOR could induce autophagy [29]. All the above results indicated that YAP knock-down could induce autophagy by inhibiting activation of Akt/mTOR signaling pathway.…”

“Repair Me if You Can”: Membrane Damage, Response, and Control from the Viral Perspective

“…A partial explanation for this observation might be that Gal3 initially promotes interactions between ALIX and the downstream ESCRT-III effector CHMP4. At later times, however, Gal3 controls the autophagic response via TRIM16 supported by Gal8/9 that regulate mTOR/AMPK [ 133 ]. A very recent study showed that macrophages challenged with either invasive bacteria or LLOMe activates the Parkinson’s disease related kinase leucine-rich repeat kinase 2 (LRKK2), which in turn recruits the Rab GTPase Rab8A.…”

“…The interplay of Gal3/8/9 with the ESCRT machinery, autophagy and metabolic signaling is also observed during membrane damage upon M. tuberculosis and Coxiella burnetii infection [ 129 , 133 ]. Interestingly, mycobacterial effectors EsxG/TB9.8 and EsxH/TB10.4 secreted by the ESX-3 T7SS secretion system antagonize the ESCRT response with a kinetic that matches the speed with which the cell responds, showing that bacteria have also developed efficient countermeasures against membrane repair mechanisms [ 135 ].…”