An AMPKα2-specific phospho-switch controls lysosomal targeting for activation.

Autor:	Morrison KR; Flinders Health and Medical Research Institute, Flinders University, Adelaide, SA 5042, Australia., Smiles WJ; Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, VIC 3065, Australia., Ling NXY; Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, VIC 3065, Australia., Hoque A; Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, VIC 3065, Australia., Shea G; Flinders Health and Medical Research Institute, Flinders University, Adelaide, SA 5042, Australia., Ngoei KRW; Protein Chemistry & Metabolism Unit, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, VIC 3065, Australia., Yu D; Protein Chemistry & Metabolism Unit, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, VIC 3065, Australia., Murray-Segal L; Protein Chemistry & Metabolism Unit, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, VIC 3065, Australia., Scott JW; Protein Chemistry & Metabolism Unit, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, VIC 3065, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Fitzroy, VIC 3000, Australia; The Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, VIC 3052, Australia., Galic S; Protein Chemistry & Metabolism Unit, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, VIC 3065, Australia., Kemp BE; Protein Chemistry & Metabolism Unit, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, VIC 3065, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Fitzroy, VIC 3000, Australia., Petersen J; Flinders Health and Medical Research Institute, Flinders University, Adelaide, SA 5042, Australia; Nutrition and Metabolism, South Australia Health and Medical Research Institute, Adelaide, SA, Australia. Electronic address: janni.petersen@flinders.edu.au., Oakhill JS; Metabolic Signalling Laboratory, St Vincent's Institute of Medical Research, School of Medicine, University of Melbourne, Melbourne, VIC 3065, Australia. Electronic address: joakhill@svi.edu.au.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2022 Feb 15; Vol. 38 (7), pp. 110365.
DOI:	10.1016/j.celrep.2022.110365
Abstrakt:	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 α-isoforms. We report that genetic or torin1-induced loss of α2-S345 phosphorylation relieves suppression of AMPK signaling; however, the regulatory effect does not translate to α1-S347 in HEK293T or MEF cells. Dephosphorylation of α2-S345, but not α1-S347, transiently targets AMPK to lysosomes, a cellular site for activation by LKB1. By mass spectrometry, we find that α2-S345 is basally phosphorylated at 2.5-fold higher stoichiometry than α1-S347 in HEK293T cells and, unlike α1, phosphorylation is partially retained after prolonged mTORC1 inhibition. Loss of α2-S345 phosphorylation in endogenous AMPK fails to sustain growth of MEFs under amino acid starvation conditions. These findings uncover an α2-specific mechanism by which AMPK can be activated at lysosomes in the absence of changes in cellular energy. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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