MAP4K3 inhibits Sirtuin-1 to repress the LKB1-AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex
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 pa...
Saved in:
Published in | Life science alliance Vol. 6; no. 8; p. e202201525 |
---|---|
Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Life Science Alliance LLC
01.08.2023
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Mary Rose Branch, Cynthia L Hsu, and Kohta Ohnishi are co-first authors Kohta Ohnishi’s present address is Laboratory of Animal Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan |
ISSN: | 2575-1077 2575-1077 |
DOI: | 10.26508/lsa.202201525 |