Galectins Control mTOR in Response to Endomembrane Damage

Area of Science:

• Cellular Biology
• Molecular Signaling
• Immunology

Background:

• The mechanistic target of rapamycin (mTOR) kinase regulates metabolic pathways, including autophagy.
• Autophagy is crucial for maintaining cellular and organelle homeostasis, beyond its catabolic roles.
• The signaling mechanisms linking endomembrane damage to mTOR-mediated autophagic responses remain unclear.

Purpose of the Study:

• To investigate how lysosomal damage signals are transmitted to mTOR to regulate autophagy.
• To identify the molecular players involved in sensing lysosomal damage and initiating cellular responses.

Main Methods:

• Investigated the role of galectins in sensing lysosomal damage.
• Examined the association of galectins with the mTOR signaling complex on lysosomes.
• Analyzed the impact of lysosomal damage on mTOR activity, AMPK activation, and downstream effectors like autophagy.

Main Results:

• Lysosomal damage inhibits mTOR activity, mediated by the association of galectin-8 (Gal8) with the lysosomal mTOR apparatus.
• Galectin-8 inhibits mTOR via the Ragulator-Rag signaling pathway.
• Galectin-9 activates AMP-activated protein kinase (AMPK) in response to lysosomal injury, converging with mTOR pathways on autophagy and defense against Mycobacterium tuberculosis.

Conclusions:

• A novel galectin-based signal-transduction system, termed GALTOR, has been identified.
• GALTOR intersects with known mTOR regulators at the lysosome, controlling cellular responses to damage.
• This pathway is critical for orchestrating autophagy and immune defense following lysosomal injury.