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ATF4 regulates mTORC1 responses to prolonged leucine deprivation via REDD1 and Sestrin2

The master protein kinase, mechanistic target of rapamycin complex 1 (mTORC1), promotes anabolism when it is activated by amino acids, particularly leucine, and suppresses catabolism when its activity is reduced by amino acid deprivation.  Amino acid deprivation leads to catabolic processes, including autophagy, leading to the availability of substrates for metabolism and the release of amino acids from cellular proteins.  The amino acids generated by autophagy could restore anabolic processes unless there are mechanisms to prevent the reactivation of mTORC1 during limiting nutrient situations.  Recent studies have determined that regulation in development and DNA damage response 1 (REDD1), activating transcription factor 4 (ATF4), and Sestrin2 are involved in regulating the reactivation of mTORC1.  However, it is unclear whether REDD1, ATF4, and Sestrin2 are involved in suppression of mTORC1 activity during periods of prolonged amino acid (leucine) deprivation.  A study testing this hypothesis was conducted by Xu and colleagues and they published their results in the May 2020 issue of The Journal of Nutrition.

Young mice (8 wk old) were food deprived overnight and half of the animals were provided food in the morning.  Liver samples were collected to determine mTORC1 activity, and the expression of ATF4, REDD1, and Sestrin2.  In addition, mouse embryo fibroblasts deficient in ATF4, REDD1, and/or Sestrin2 were cultured and deprived of leucine for up to 16 hours.  The same variables measured in the mice were also determined in the fibroblasts.

The activity of mTORC1 was elevated and the expression of REDD1 and Sestrin2 was suppressed in the liver of mice that were refed.  Leucine deprivation of fibroblasts initially suppressed mTORC1, which was reactivated from 2-4 hours, and by 8 hours it was suppressed again.  The resuppression occurred in concert with an upregulation of ATF4, REDD1, and Sestrin2.  Cells lacking ATF4 did not exhibit an increase in REDD1 or Sestrin2 expression upon leucine deprivation and the subsequent suppression of mTORC1 did not occur.  The absence of REDD1 and Sestrin2 led to an attenuated suppression of mTORC1.  The authors concluded that mTORC1 is suppressed during prolonged periods of leucine deprivation via upregulation of REDD1 and Sestrin2, processes that are mediated by ATF4.

In a commentary on this article, Rasmussen and Adams describe the key processes involved in the regulation of cellular processes in response to amino acid presence or absence.  This description provided context to the work conducted by Xu and colleagues.  They found the work by Xu and colleagues to be intriguing and describe the need to conduct additional studies to explore the roles of these regulatory processes in muscle and liver in vivo, and determine if they are involved in muscle atrophy.

References Xu D, Dai W, Kutzler L, Lacko HA, Jefferson LS, Dennis MD, Kimball SR. ATF4-mediated upregulation of REDD1 and Sestrin2 suppresses mTORC1 activity during prolonged leucine deprivation.  Journal of Nutrition, Volume 150, Issue 5, May 2020, Pages 1022–1030, DOI: https://doi.org/10.1093/jn/nxz309.

Rasmussen BB, Adams CM. ATF4 is a fundamental regulator of nutrient sensing and protein turnover.  Journal of Nutrition, Volume 150, Issue 5, May 2020, Pages 979–980, https://doi.org/10.1093/jn/nxaa067.

Images credit: canva.com

Nancy Turner, PhD

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