Sestrin2 is a leucine sensor for the mTORC1 pathway

Abstract

Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex 1 (mTORC1) protein kinase, a master growth controller. Amino acids signal to mTORC1 through the Rag guanine triphosphatases (GTPases). Several factors regulate the Rags, including GATOR1, a GTPase activating protein (GAP); GATOR2, a positive regulator of unknown function; and Sestrin2, a GATOR2-interacting protein that inhibits mTORC1 signaling. We find that leucine, but not arginine, disrupts the Sestrin2-GATOR2 interaction by binding to Sestrin2 with a Kd of 20 µM, which is the leucine concentration that half-maximally activates mTORC1. The leucine-binding capacity of Sestrin2 is required for leucine to activate mTORC1 in cells. These results indicate that Sestrin2 is a leucine sensor for the mTORC1 pathway.

mTOR Signaling in Growth, Metabolism, and Disease

“…Subsequent biochemical and structural analyses established that Sestrin2 is a direct leucine sensor upstream of mTORC1 that binds and inhibits GATOR2 function in the absence of leucine, and dissociates from it upon leucine binding (Saxton et al, 2016a;Wolfson et al, 2016). Furthermore, the affinity of Sestrin2 for leucine determines the sensitivity of mTORC1 signaling to leucine in cultured cells, demonstrating that Sestrin2 is the primary leucine sensor for mTORC1 in this context.…”

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…Glutamine can contribute to mTORC1 activation by being exchanged for essential amino acids, including leucine, through the large neutral amino acid transporter 1 (LAT1; a heterodimer of SLC7A5 and SLC3A2) transporter 17 . This RAG-dependent regulation of mTOR is likely dependent on the lysosomal amino acid transporter SLC38A9, which transports glutamine, arginine, and leucine as substrates 129,132,133 , as well as the leucine sensor sestrin 2 (not shown in Figure) 217,218 . Although the mechanism is not well understood, α-ketoglutarate (α-KG) may regulate RAGB activity and mTOR activation downstream of glutamine metabolism 219 .…”

Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex

“…Binding to Raptor requires RagA/B to be GTP loaded, while RagC/D must be GDP loaded. Nutrients are thought to induce the RagA/B GTP -RagC/D GDP active state via a series of dedicated sensors that, in turn, control GTPase Activating Proteins (GAPs) and guanine nucleotide exchange factors (GEFs) specific for either Rag component (Bar-Peled et al, 2012;Barad et al, 2015;Chantranupong et al, 2016;Saxton et al, 2016;Wolfson et al, 2016;Zoncu et al, 2011). For example, the Gator1 complex has been shown to function as a GAP that promotes GTP hydrolysis by RagA/B, thus causing mTORC1 detachment from the lysosome when nutrient levels are low Panchaud et al, 2013).…”