Molecular Cell
Volume 70, Issue 1, 5 April 2018, Pages 120-135.e8
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Article
Galectins Control mTOR in Response to Endomembrane Damage

https://doi.org/10.1016/j.molcel.2018.03.009Get rights and content
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Highlights

  • Lysosomal damage inhibits mTOR through a galectin-based system termed GALTOR

  • Galectin-8 inhibits mTOR via interactions with the Ragulator-Rag SLC38A9 system

  • Lysosomal damage activates AMPK through galectin-9 with the engagement of TAK1

  • Galectins control autophagy in response to lysosomal damage via mTOR and AMPK

Summary

The Ser/Thr protein kinase mTOR controls metabolic pathways, including the catabolic process of autophagy. Autophagy plays additional, catabolism-independent roles in homeostasis of cytoplasmic endomembranes and whole organelles. How signals from endomembrane damage are transmitted to mTOR to orchestrate autophagic responses is not known. Here we show that mTOR is inhibited by lysosomal damage. Lysosomal damage, recognized by galectins, leads to association of galectin-8 (Gal8) with the mTOR apparatus on the lysosome. Gal8 inhibits mTOR activity through its Ragulator-Rag signaling machinery, whereas galectin-9 activates AMPK in response to lysosomal injury. Both systems converge upon downstream effectors including autophagy and defense against Mycobacterium tuberculosis. Thus, a novel galectin-based signal-transduction system, termed here GALTOR, intersects with the known regulators of mTOR on the lysosome and controls them in response to lysosomal damage.

Keywords

mTOR
AMPK
autophagy
galectins
lysosome
catabolism
TFEB
LC3
APEX2
TAK1

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