title: A Critical SUMO1 Modification of LKB1 Regulates AMPK Activity during Energy Stress.
abstract: SUMOylation has been implicated in cellular stress adaptation, but its role in regulating liver kinase B1 (LKB1), a major upstream kinase of the energy sensor AMP-activated protein kinase (AMPK), is unknown. Here, we show that energy stress triggers an increase in SUMO1 modification of LKB1, despite a global reduction in both SUMO1 and SUMO2/3 conjugates. During metabolic stress, SUMO1 modification of LKB1 lysine 178 is essential in promoting its interaction with AMPK via a SUMO-interacting motif (SIM) essential for AMPK activation. The LKB1 K178R SUMO mutant had defective AMPK signaling and mitochondrial function, inducing death in energy-deprived cells. These results provide additional insight into how LKB1-AMPK signaling is regulated during energy stress, and they highlight the critical role of SUMOylation in maintaining the cell's energy equilibrium.
authors.affiliation: Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Ritho
authors.affiliation: Computational Bioscience Research Center, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia.
authors.forename: Stefan T
authors.initials: ST
authors.lastname: Arold
authors.affiliation: Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: etyeh@mdanderson.org.
authors.forename: Edward T H
authors.initials: ET
authors.lastname: Yeh
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D004734:Energy Metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D058207:Sumoylation
chemical_list: D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases