Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) kinase controls growth in response to nutrients, including the amino acid leucine. In cultured cells, mTORC1 senses leucine through the leucine-binding Sestrin proteins, but the physiological functions and distribution of Sestrin-mediated leucine sensing in mammals are unknown. We find that mice lacking Sestrin1 and Sestrin2 cannot inhibit mTORC1 upon dietary leucine deprivation and suffer a rapid loss of white adipose tissue (WAT) and muscle. The WAT loss is driven by aberrant mTORC1 activity and fibroblast growth factor 21 (FGF21) production in the liver. Sestrin expression in the liver lobule is zonated, accounting for zone-specific regulation of mTORC1 activity and FGF21 induction by leucine. These results establish the mammalian Sestrins as physiological leucine sensors and reveal a spatial organization to nutrient sensing by the mTORC1 pathway.

Leucine alleviates cytokine storm syndrome by regulating macrophage polarization via the mTORC1/LXRα signaling pathway

“…A key effector of leucine is believed to activate the mTORC1 protein kinase (Cangelosi et al, 2022). In our study, inhibiting mTORC1 was found to suppress Arg1 expression and inhibit leucine-mediated M2 polarization (Figure 4A and Supplement Figure 3A).…”

Cell Type-Specific Metabolic Response to Amino Acid Starvation Dictates the Role of Sestrin2 in Regulation of mTORC1

“…The complex cellular response observed upon glutamine starvation suggests a complementary regulation of mTORC1 through several pathways [ 43 ]. In contrast, direct leucine sensing of Sestrin2 could be a reason for a more selective Sestrin2-dependent inhibition of mTORC1 for this branch of amino acid utilization/metabolism [ 21 , 44 , 45 ]. Glutamine deprivation causes leucine accumulation in glutamine-deprived pancreatic cancer cells [ 35 ], which could disrupt the Sestrin2:GATOR2 complex important for Sestrin2-dependent mTORC1 inhibition.…”

The human LAT1–4F2hc (SLC7A5–SLC3A2) transporter complex: Physiological and pathophysiological implications

“…Free leucine can bind to Sestrin1/2, causing their conformational changes, which leads to the dissociation of GATOR2 (GAP activity towards Rags complex 2). [80][81][82] GATOR2 is now able to F I G U R E 2 LAT1-4F2hc in mTORC1 signalling and the intergraded stress response. Cartoon showing components of the nutrientsensing as well as growth factor sensing pathway upstream of mTORC1.…”

“…Among those, the essential amino acid leucine is particularly important to activate mTORC1. Free leucine can bind to Sestrin1/2, causing their conformational changes, which leads to the dissociation of GATOR2 (GAP activity towards Rags complex 2) 80–82 . GATOR2 is now able to inhibit GATOR1, a conserved GAP (GTPase‐activating protein) for Rag A/B.…”