Title: An AMPKa2-specific phospho-switch controls lysosomal targeting for activation
Authors: Morrison, KR
Smiles, WJ
Ling, NXY
Hoque, A
Shea, G
Ngoei, KRW
Yu, DY
Murray-Segal, L
Scott, JW
Galic, S
Kemp, BE
Petersen, J
Oakhill, JS
Issue Year: 2022
Publisher CELL PRESS
Abstract AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) are metabolic kinases that co-ordinate nutrient supply with cell growth. AMPK negatively regulates mTORC1, and mTORC1 reciprocally phosphorylates S345/7 in both AMPK a-isoforms. We report that genetic or torin1induced loss of a2-S345 phosphorylation relieves suppression of AMPK signaling; however, the regulatory effect does not translate to a1-S347 in HEK293T or MEF cells. Dephosphorylation of a2-S345, but not a1 S347, transiently targets AMPK to lysosomes, a cellular site for activation by LKB1. By mass spectrometry, we find that a2-S345 is basally phosphorylated at 2.5-fold higher stoichiometry than a1-S347 in HEK293T cells and, unlike a1, phosphorylation is partially retained after prolonged mTORC1 inhibition. Loss of a2 S345 phosphorylation in endogenous AMPK fails to sustain growth of MEFs under amino acid starvation conditions. These findings uncover an a2-specific mechanism by which AMPK can be activated at lysosomes in the absence of changes in cellular energy.
URI: https://publications.svi.edu.au/publications/8053
Other Identifiers 10.1016/j.celrep.2022.110365
Publication type Article