MAP4K3 inhibits Sirtuin-1 to repress the LKB1-AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex.

Autor:	Branch MR; Departments of Pathology & Laboratory Medicine, Neurology, and Biological Chemistry, University of California, Irvine, CA, USA.; Department of Neurology, Duke University School of Medicine, Durham, NC, USA., Hsu CL; Department of Pediatrics, University of California, San Diego; La Jolla, CA, USA., Ohnishi K; Department of Pediatrics, University of California, San Diego; La Jolla, CA, USA., Shen WC; Departments of Pathology & Laboratory Medicine, Neurology, and Biological Chemistry, University of California, Irvine, CA, USA., Lee E; Department of Pediatrics, University of California, San Diego; La Jolla, CA, USA., Meisenhelder J; Molecular and Cellular Biology Laboratory, Salk Institute, La Jolla, CA, USA., Winborn B; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Sopher BL; Department of Pathology, University of Washington Medical Center, Seattle, WA, USA., Taylor JP; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Howard Hughes Medical Institute, Chevy Chase, MD, USA., Hunter T; Molecular and Cellular Biology Laboratory, Salk Institute, La Jolla, CA, USA., La Spada AR; Departments of Pathology & Laboratory Medicine, Neurology, and Biological Chemistry, University of California, Irvine, CA, USA alaspada@uci.edu.; Department of Neurology, Duke University School of Medicine, Durham, NC, USA.; Department of Pediatrics, University of California, San Diego; La Jolla, CA, USA.; UCI Institute for Neurotherapeutics, University of California, Irvine, CA, USA.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2023 May 23; Vol. 6 (8). Date of Electronic Publication: 2023 May 23 (Print Publication: 2023).
DOI:	10.26508/lsa.202201525
Abstrakt:	mTORC1 is the key rheostat controlling the cellular metabolic state. Of the various inputs to mTORC1, the most potent effector of intracellular nutrient status is amino acid supply. Despite an established role for MAP4K3 in promoting mTORC1 activation in the presence of amino acids, the signaling pathway by which MAP4K3 controls mTORC1 activation remains unknown. Here, we examined the process of MAP4K3 regulation of mTORC1 and found that MAP4K3 represses the LKB1-AMPK pathway to achieve robust mTORC1 activation. When we sought the regulatory link between MAP4K3 and LKB1 inhibition, we discovered that MAP4K3 physically interacts with the master nutrient regulatory factor sirtuin-1 (SIRT1) and phosphorylates SIRT1 to repress LKB1 activation. Our results reveal the existence of a novel signaling pathway linking amino acid satiety with MAP4K3-dependent suppression of SIRT1 to inactivate the repressive LKB1-AMPK pathway and thereby potently activate the mTORC1 complex to dictate the metabolic disposition of the cell. (© 2023 Branch et al.)
Databáze:	MEDLINE
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