The mechanistic target of rapamycin in complex 1 (mTORC1) is a regulator of cell growth and metabolism. Prior work has identified Sestrins as proximal sensors for leucine activation of mTORC1. However, it is currently not known if Sestrins also mediate the activation of mTORC1 by glucose. Roberson and colleagues conducted a study to determine if this is the case and report the results of their study in the April 2023 issue of The Journal of Nutrition.
The research was conducted using a rodent model and cell culture experiments. Fasted rats were gavaged with either a saline or glucose solution (4 g.kg-1 BW/10 ml.kg-1) prior to determining mTORC1 activation in the tibialis anterior muscle. Cell lines used included wild-type HEK293T cells or HEK293T cells lacking all three Sestrins or hexokinase 2. Cells were incubated in media without glucose for 3 hours prior to having glucose added back for 30 minutes prior to measuring mTORC1 activation, and the association of Sestrins with components of GAP activity toward the Rags (GATOR2) complex and hexokinase 2.
Glucose treatment promoted mTORC1 activation in fasted rats and glucose deprived wild type cells. However, Sestrin knockout cells did not achieve the same level of activation once glucose was added back as the wild type cells. Hexokinase 2 association with each of the 3 Sestrins was elevated with glucose deprivation and decreased with glucose addition in wild type cells. Addition of glucose to hexokinase 2 knockout cells resulted in an attenuated response, compared to the wild type cells. The authors concluded that both Sestrins and hexokinase 2 are important regulators of glucose-induced mTORC1 activation, but the effect was independent of interactions between Sestrin and GATOR2 and dependent on association of Sestrins with hexokinase 2.
In an editorial, Azzout-Marniche provides a description of the multiple processes regulated by mTOR signaling, and the various signal initiators and effectors involved. Azzout-Marniche also describes the results from Roberson and colleagues that led to the identification of a new mechanism involving regulation by Sestrin leading to differential regulation of metabolism through mTOR signaling by leucine and glucose.
Roberson PA, Kincheloe GN, Welles JE, Xu D, Sam-Clarke M, MacLean PS, et al. Glucose-induced activation of mTORC1 is associated with hexokinase2 binding to Sestrins in HEK293T cells. Journal of Nutrition, Volume 153, Issue 4, April 2023, Pages 988-998, doi.org/10.1016/j.tjnut.2022.11.021.
Azzout-Marniche D. New insight into the understanding of muscle glycolysis: Sestrins, key pivotal proteins integrating glucose and leucine to control mTOR activation. Journal of Nutrition, Volume 153, Issue 4, April 2023, Pages 915-916, doi.org/10.1016/j.tjnut.2023.01.029.
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