ATF4: A stress-responsive factor in mTORC1 signaling

Vaishnavi Kardale, Bioinformatics Centre, Savitribai Phule Pune University

For a very long time, researchers have been searching for ways to increase human life. In this quest, they have found one promising protein -mTOR. The finding of mTOR has given rise to a whole field in cellular biology that studies mTOR and its associated pathway. 

mTOR- A CPU that responds to input:

The story begins with the finding of Rapamycin. Suren N Sehgal – widely considered the father of rapamycin was searching for new antibiotics in the soil. In 1975, he purified the compound from Easter Island also known as Rapa Nui. Initially discovered as an antifungal, its role as an immunosuppressive and an anti-cell proliferative was unknown. To understand the cellular pathway of rapamycin, David Sabatini began his work and isolated mTOR. 

Mechanistic Target of Rapamycin (mTOR) has been found to be a protein that is highly conserved. It is at the center of a lot of cellular processes. mTOR is primarily responsible for cell growth and proliferation and responds to a number of factors like nutrients, oxygen stress, fasting and feeding state, insulin levels, and growth factors. It promotes protein and lipid synthesis and suppresses autophagy. David Sabatini describes mTOR as a CPU that sits at the center that responds according to the input. 

Why mTOR?

Significant research has been found that suggests that the inhibition of mTOR can slow down aging and age-associated diseases. Its role in cell proliferation is being inspected by cancer biologists. mTOR inhibition led to longevity in model organisms. mTOR regulates many downstream cellular processes; research is being carried out to better understand them.

A Study to analyze mTORC1 signaling:

ATF4, a stress-responsive transcription factor, was found to be regulated by mTORC1 signaling in growing cells. ATF4’s role was investigated to determine whether it is responsive to mTORC1 signaling to alter hepatocyte metabolism. To do this, researchers analyzed ATF4 protein levels and their canonical gene targets in the liver after physiological fasting and feeding in the presence and absence of mTORC1 inhibitor rapamycin.  To characterize the effect of insulin-stimulated mTORC1- ATF4 function on hepatocyte metabolism, hepatocytes from wild-type and liver-specific Atf4 knockout mice were used.

What did the study find?

The study found that mTORC1 signaling in the liver stimulates ATF4 and its metabolic gene target in response to feeding and insulin. The study also found that de novo purine and pyrimidine synthesis was stimulated, independent of ATF4, by insulin through mTORC1 signaling. Metabolomic studies revealed that non-essential amino acid synthesis in the liver cells was stimulated by insulin-mTORC1-ATF4 signaling. 

Conclusion:

ATF4 was found to be a novel effector of hepatic mTORC1 signaling in response to insulin. There may be more downstream mediators of the mTORC1 that are yet to be defined. This study helps us understand how mTORC1 exerts metabolic control.  It is of particular interest that in the case of obesity both ATF4 and mTORC1 are upregulated. 

Also read: Antibiotic-Resistant Bacteremia affects children with pneumonia

Reference:

1. Byles, V., Cormerais, Y., Kalafut, K., Barrera, V., Hughes Hallett, J. E., Ho Sui, S., Asara, J. M., Adams, C. M., Hoxhaj, G., Sahra, I. B., & Manning, B. D. (2021). Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin. Molecular Metabolism. Published. https://doi.org/10.1016/j.molmet.2021.101309

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Author info:

Vaishnavi Kardale is a master’s student at the Bioinformatics Centre, Savitribai Phule University. She is interested in protein folding mechanisms and wants to study them further.

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