Sestrin regulation of TORC1: Is Sestrin a leucine sensor?

Sestrin2 may not be a leucine sensor for mTORC1. Gloss Environmental and metabolic stresses, such as DNA damage and nutrient deprivation, induce the expression of evolutionarily conserved proteins called Sestrins. In both flies and mammals, Sestrin inhibits the nutrient-responsive protein kinase complex target of rapamycin complex 1 (TORC1), which regulates the biosynthesis of macromolecules including proteins, lipids, and nucleic acids. The mechanisms through which Sestrins inhibit TORC1 activity are both indirect, depending on activation of the adenosine monophosphate (AMP)–activated protein kinase (AMPK), and direct, mediated through interaction with the TORC1-regulating protein complex GATOR. New findings suggest that the ability of Sestrins to interact with GATOR is regulated by the amino acid leucine. Here, we discuss whether and how this finding fits what has already been learned about the physiological functions of Sestrin in mammals and insects. Sestrins are highly conserved, stress-inducible proteins that inhibit target of rapamycin complex 1 (TORC1) signaling. After their transcriptional induction, both vertebrate and invertebrate Sestrins turn on the adenosine monophosphate (AMP)–activated protein kinase (AMPK), which activates the tuberous sclerosis complex (TSC), a key inhibitor of TORC1 activation. However, Sestrin overexpression, on occasion, can result in TORC1 inhibition even in AMPK-deficient cells. This effect has been attributed to Sestrin’s ability to bind the TORC1-regulating GATOR2 protein complex, which was postulated to control trafficking of TORC1 to lysosomes. How the binding of Sestrins to GATOR2 is regulated and how it contributes to TORC1 inhibition are unknown. New findings suggest that the amino acid leucine specifically disrupts the association of Sestrin2 with GATOR2, thus explaining how leucine and related amino acids stimulate TORC1 activity. We discuss whether and how these findings fit what has already been learned about Sestrin-mediated TORC1 inhibition from genetic studies conducted in fruit flies and mammals.