A Critical SUMO1 Modification of LKB1 Regulates AMPK Activity during Energy Stress

• SUMO1 conjugation of LKB1 increases as intracellular ATP levels decline
• During energy stress, lysine 178 of LKB1 is a critical SUMO1 conjugation site
• SUMO1 modification of LKB1 enables the recognition and activation of AMPK via a SIM
• LKB1 K178R SUMO mutant is defective in AMPK activation and downstream signaling

SummarySUMOylation 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.

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