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

• Published in: Molecular cell 2020-03, Vol.77 (5), p.951-969.e9
• Main Authors: Jia, Jingyue, Bissa, Bhawana, Brecht, Lukas, Allers, Lee, Choi, Seong Won, Gu, Yuexi, Zbinden, Mark, Burge, Mark R., Timmins, Graham, Hallows, Kenneth, Behrends, Christian, Deretic, Vojo
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; autophagosome; Autophagy - drug effects; diabetes; Energy Metabolism - drug effects; Enzyme Activation; ESCRT; Female; Galectins - genetics; Galectins - metabolism; HEK293 Cells; HeLa Cells; Humans; Hypoglycemic Agents - pharmacology; LKB1; Lysosomes - drug effects; Lysosomes - enzymology; Lysosomes - microbiology; Lysosomes - pathology; Male; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; metabolism; metformin; Metformin - pharmacology; Mice, Inbred C57BL; Mice, Knockout; Mycobacterium tuberculosis - pathogenicity; Signal Transduction; TAK1; THP-1 Cells; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TOR; TRAIL; tuberculosis; Ubiquitin - metabolism; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; Ubiquitination; Young Adult
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.12.028

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. [Display omitted] •Lysosomal damage activates AMPK, autophagy, and metabolic and antimicrobial responses•Galectin 9 transduces damage signal to ubiquitin responses via USP9X and TAK1•TAK1 controls AMPK in the physiological context of lysosomal permeability changes•Anti-diabetic drug metformin causes mild lysosomal damage and downstream responses Jia, Bissa, Brecht et al. show that AMPK is activated upon lysosomal damage caused by microbes, ligands such as TRAIL, and other agents including the anti-diabetes drug metformin, via a novel signal transduction system from galectins to ubiquitin and that this results in the activation of AMPK by TAK1.