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

Jingyue Jia; Bhawana Bissa; Lukas Brecht; Lee Allers; Seong Won Choi; Yuexi Gu; Mark Zbinden; Mark R Burge; Graham Timmins; Kenneth Hallows; Christian Behrends; Vojo Deretic

doi:10.1016/j.molcel.2019.12.028

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.

Authors

Affiliations

¹ Autophagy, Inflammation and Metabolism AIM Center of Biochemical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM, USA; Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
² Munich Cluster of Systems Neurology, Munich, Germany.
³ Human Metabolome Technologies America, Boston, MA, USA.
⁴ Autophagy, Inflammation and Metabolism AIM Center of Biochemical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM, USA; Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.
⁵ Autophagy, Inflammation and Metabolism AIM Center of Biochemical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM, USA; School pf Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
⁶ Division of Nephrology and Hypertension, Department of Medicine and USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷ Autophagy, Inflammation and Metabolism AIM Center of Biochemical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM, USA; Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, USA. Electronic address: [email protected].

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
PRKAA2 protein, human
MAP Kinase Kinase Kinases
MAP kinase kinase kinase 7
AMP-Activated Protein Kinases
PRKAA1 protein, human
Ubiquitin Thiolesterase
Usp9x protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding