SUMOylation of AMPKα1 by PIAS4 specifically regulates mTORC1 signalling

• Published in: Nature communications Vol. 6; no. 1; p. 8979
• Main Authors: Yan, Yan, Ollila, Saara, Wong, Iris P. L., Vallenius, Tea, Palvimo, Jorma J., Vaahtomeri, Kari, Mäkelä, Tomi P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.11.2015; Nature Pub. Group
• Subjects: 13/1; 13/106; 13/109; 13/89; 13/95; 14/1; 14/63; 631/67/1347; 631/80/458/538; 631/80/83/2359; 82/111; 82/29; 82/80; 82/83; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Humanities and Social Sciences; Humans; Mechanistic Target of Rapamycin Complex 1; multidisciplinary; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Phosphorylation; Poly-ADP-Ribose Binding Proteins; Protein Inhibitors of Activated STAT - genetics; Protein Inhibitors of Activated STAT - metabolism; Science; Science (multidisciplinary); Signal Transduction; Sumoylation; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms9979

AMP-activated protein kinase (AMPK) inhibits several anabolic pathways such as fatty acid and protein synthesis, and identification of AMPK substrate specificity would be useful to understand its role in particular cellular processes and develop strategies to modulate AMPK activity in a substrate-specific manner. Here we show that SUMOylation of AMPKα1 attenuates AMPK activation specifically towards mTORC1 signalling. SUMOylation is also important for rapid inactivation of AMPK, to allow prompt restoration of mTORC1 signalling. PIAS4 and its SUMO E3 ligase activity are specifically required for the AMPKα1 SUMOylation and the inhibition of AMPKα1 activity towards mTORC1 signalling. The activity of a SUMOylation-deficient AMPKα1 mutant is higher than the wild type towards mTORC1 signalling when reconstituted in AMPKα-deficient cells. PIAS4 depletion reduced growth of breast cancer cells, specifically when combined with direct AMPK activator A769662, suggesting that inhibiting AMPKα1 SUMOylation can be explored to modulate AMPK activation and thereby suppress cancer cell growth. AMPK senses cellular energy and switches off pathways involved in protein and fatty acid synthesis, but the selectivity of AMPK for different pathways is unclear. Here, the authors show that PIAS4-dependent SUMOylation and inactivation of AMPK preferentially restores activity of the mTORC1 pathway.