Sestrin regulation of TORC1: Is Sestrin a leucine sensor?

Lee, Jun Hee; Cho, Uhn-Soo; Karin, Michael

doi:10.1126/scisignal.aaf2885

Sestrin regulation of TORC1: Is Sestrin a leucine sensor?

Journal Article · Tue Jun 07 00:00:00 EDT 2016 · Science Signaling

DOI:https://doi.org/10.1126/scisignal.aaf2885· OSTI ID:1351357

Lee, Jun Hee ^[1]; Cho, Uhn-Soo ^[1]; Karin, Michael ^[2]

Univ. of Michigan, Ann Arbor, MI (United States)
Univ. of California, San Diego, CA (United States)

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. Finally, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE

OSTI ID:: 1351357

Journal Information:: Science Signaling, Journal Name: Science Signaling Journal Issue: 431 Vol. 9; ISSN 1945-0877

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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