SUMOylation of AMPKa1 by PIAS4 specifically regulates mTORC1 signalling.

Nature communications

PubMedID: 26616021

Yan Y, Ollila S, Wong IP, Vallenius T, Palvimo JJ, Vaahtomeri K, Mäkelä TP. SUMOylation of AMPKa1 by PIAS4 specifically regulates mTORC1 signalling. Nat Commun. 2015;68979.
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 AMPKa1 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 AMPKa1 SUMOylation and the inhibition of AMPKa1 activity towards mTORC1 signalling. The activity of a SUMOylation-deficient AMPKa1 mutant is higher than the wild type towards mTORC1 signalling when reconstituted in AMPKa-deficient cells. PIAS4 depletion reduced growth of breast cancer cells, specifically when combined with direct AMPK activator A769662, suggesting that inhibiting AMPKa1 SUMOylation can be explored to modulate AMPK activation and thereby suppress cancer cell growth.