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Sci Signal. 2016 Jun 7;9(431):re5. doi: 10.1126/scisignal.aaf2885.

Sestrin regulation of TORC1: Is Sestrin a leucine sensor?

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Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
Departments of Pharmacology and Pathology, University of California, San Diego, School of Medicine, La Jolla, CA 92093-0723, USA.


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.

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