AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal Damage via a Novel Galectin-Directed Ubiquitin Signal Transduction System

Mol Cell. 2020 Mar 5;77(5):951-969.e9. doi: 10.1016/j.molcel.2019.12.028. Epub 2020 Jan 28.

Abstract

AMPK is a central regulator of metabolism and autophagy. Here we show how lysosomal damage activates AMPK. This occurs via a hitherto unrecognized signal transduction system whereby cytoplasmic sentinel lectins detect membrane damage leading to ubiquitination responses. Absence of Galectin 9 (Gal9) or loss of its capacity to recognize lumenal glycans exposed during lysosomal membrane damage abrogate such ubiquitination responses. Proteomic analyses with APEX2-Gal9 have revealed global changes within the Gal9 interactome during lysosomal damage. Gal9 association with lysosomal glycoproteins increases whereas interactions with a newly identified Gal9 partner, deubiquitinase USP9X, diminishes upon lysosomal injury. In response to damage, Gal9 displaces USP9X from complexes with TAK1 and promotes K63 ubiquitination of TAK1 thus activating AMPK on damaged lysosomes. This triggers autophagy and contributes to autophagic control of membrane-damaging microbe Mycobacterium tuberculosis. Thus, galectin and ubiquitin systems converge to activate AMPK and autophagy during endomembrane homeostasis.

Keywords: ESCRT; LKB1; TAK1; TOR; TRAIL; autophagosome; diabetes; metabolism; metformin; tuberculosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Adolescent
  • Adult
  • Animals
  • Autophagy* / drug effects
  • Energy Metabolism* / drug effects
  • Enzyme Activation
  • Female
  • Galectins / genetics
  • Galectins / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Lysosomes / drug effects
  • Lysosomes / enzymology*
  • Lysosomes / microbiology
  • Lysosomes / pathology
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Male
  • Metformin / pharmacology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycobacterium tuberculosis / pathogenicity
  • Signal Transduction
  • THP-1 Cells
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Ubiquitin / metabolism*
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism
  • Ubiquitination
  • Young Adult

Substances

  • Galectins
  • Hypoglycemic Agents
  • LGALS9 protein, human
  • TNF-Related Apoptosis-Inducing Ligand
  • USP9X protein, human
  • Ubiquitin
  • galectin 9, mouse
  • Metformin
  • AMPK alpha1 subunit, mouse
  • AMPK alpha2 subunit, mouse
  • PRKAA1 protein, human
  • PRKAA2 protein, human
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • AMP-Activated Protein Kinases
  • Ubiquitin Thiolesterase
  • Usp9x protein, mouse