Sestrin2
Direct intracellular leucine sensor and a NEGATIVE regulator of mTORC1. When leucine is scarce, Sestrin2 binds and inhibits GATOR2, so GATOR1 stays active and keeps mTORC1 switched off. Leucine binding (~20 uM affinity) releases GATOR2 - the pathway is switched on by removing a brake, not by adding a signal. Sestrin2 does not act on the Rag GTPases directly; it works two steps upstream, through GATOR2 and GATOR1.
A leucine detector that works as a brake. The main sensor that directly detects leucine inside the cell, and a brake on mTORC1. When leucine is scarce, it holds down GATOR2, which keeps GATOR1 active and mTORC1 switched off. Leucine coming back releases GATOR2, so this is a brake being lifted, not a new 'go' signal being added - and it works two steps upstream of the Rag GTPases, not directly on them.
Sestrin2 is a *negative* regulator. Leucine binding releases GATOR2 – the pathway is switched on by removing a brake. Also stress-inducible via p53, so it sits at a stress/nutrient junction.
TL;DR. Sestrin2 appears in 7 curated studies in Oliver's mTOR Atlas: 2 in animal models; 4 at the molecular level (cells, biochemistry, structure); 1 review. No study in people is recorded for it in the Atlas yet. It has 3 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| Sestrin2 inhibits Age-related pathology mechanism: functional-consequence · this link in full · on the map table | The only case in this atlas linking a nutrient sensor to ageing of a whole animal: fruit flies without this sensor build up fat and develop muscle and heart problems, and blocking this pathway or switching on AMPK prevents it. So the sensor holds age-related damage back. Watch what was measured – how sick the flies got, not how long they lived. Losing Drosophila Sestrin produces fat accumulation, mitochondrial dysfunction, muscle degeneration and cardiac malfunction, all prevented by inhibiting TOR or activating AMPK. Sestrin therefore limits age-associated pathology in the fly. Losing Drosophila Sestrin produces fat accumulation, mitochondrial dysfunction, muscle degeneration and cardiac malfunction, all prevented by inhibiting TOR or activating AMPK. Sestrin therefore limits age-associated pathology in the fly. Holds under: Fly only, and the readout is age-related pathology: survival was never measured. No mammalian sensor-to-ageing evidence exists in this corpus. not tested in people · emerging, few independent studies | A | LEE2010 |
| Sestrin2 inhibits GATOR2 mechanism: binding · this link in full · on the map table | When there's no leucine, Sestrin2 grabs onto GATOR2 and holds the whole growth pathway shut. When leucine is scarce, free Sestrin2 clamps onto GATOR2 and blocks it, keeping the whole pathway switched off. When leucine is scarce, free Sestrin2 clamps onto GATOR2 and blocks it, keeping the whole pathway switched off. Holds under: Mammalian cell studies (CHA2014, PAR2014, WOL2015). Shows leucine sensing in cultured cells; the importance of this sensor in whole animals and people is not tested by these studies. plausible in people, not shown directly · settled in the literature | M | CHA2014, PAR2014, WOL2015 |
| Leucine inhibits Sestrin2 mechanism: binding · this link in full · on the map table | Leucine sticks to a pocket inside Sestrin2 and makes it let go of the next protein in line – that's how the cell notices leucine is around. Leucine binds a pocket inside Sestrin2 with roughly 20 uM affinity - close to the concentration at which cells actually feel leucine coming and going. The bound sensor can no longer hold GATOR2, so leucine effectively switches the brake off. Leucine binds a pocket inside Sestrin2 with roughly 20 uM affinity - close to the concentration at which cells actually feel leucine coming and going. The bound sensor can no longer hold GATOR2, so leucine effectively switches the brake off. Holds under: Affinity was measured in vitro; whether the same 20 uM setpoint holds in tissues with different leucine transport is untested. SHIM2026 is a 2026 rat study (dexamethasone-induced muscle atrophy, not an ageing model) with human myotubes; it tests a leucine-mimetic prodrug and supports Sestrin2-dependent mTORC1 activation, not the 20 uM leucine setpoint. plausible in people, not shown directly · settled in the literature | A | WOL2015, SAX2015, SHIM2026 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| A | Animal model | 2 |
| M | Molecular — cells, biochemistry, structure | 4 |
| R | Review — secondary literature, not a new result | 1 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | A | D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia. SHIM2026 DLMEH, a D-leucine ester prodrug, binds Sestrin2 with leucine-like potency (Kd 28.3 uM, equivalent to L-leucine) and activates mTORC1 in a Sestrin2-dependent way. It restored protein synthesis in human myotubes and preserved muscle mass, grip strength and endurance in a rat dexamethasone-induced atrophy model (not an ageing sarcopenia model). |
| 2010 | A | Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies LEE2010 An early study linking Sestrin, later identified as a leucine sensor in mammals, to age-associated pathology in flies (fat accumulation, mitochondrial dysfunction, muscle and cardiac decline), prevented by TOR inhibition or AMPK activation. Sestrin sits in a negative feedback loop: TOR activity drives Sestrin expression, and Sestrin inhibits TOR back. |
| 2026 | M | ATF4 activates a transcriptional program that chronically suppresses mTOR activity and promotes neurodegeneration in Parkinson disease models DEMMINGS2026 Chronic integrated-stress-response signalling through ATF4 coordinately upregulates SESN2, DDIT4 and Trib3, which together suppress BOTH mTORC1 and mTORC2; this sustained mTOR inhibition drives dopaminergic neuron death via the pro-apoptotic BCL-2 family protein PUMA. Defines a maladaptive ISR/ATF4-to-mTOR axis in Parkinson disease models — a case where LESS mTOR activity is harmful, opposite to the usual longevity framing. |
| 2022 | M | Structure of the nutrient-sensing hub GATOR2 VAL2022 Cryo-EM structure of human GATOR2: a 1.1 MDa, two-fold symmetric cage built on an octagonal scaffold decorated with eight pairs of WD40 beta-propellers, and a map of where Sestrin2 and CASTOR1 dock. It substantially advances the GATOR2 side of the sensor module, though how GATOR2 inhibits GATOR1 is still not fully settled. |
| 2017 | R | The Dawn of the Age of Amino Acid Sensors for the mTORC1 Pathway WOLF2017 Review of the newly discovered amino-acid sensors feeding into mTORC1. |
| 2016 | M | Dynamics of mTORC1 activation in response to amino acids MAN2016 Live imaging shows mTORC1 moves to lysosomes within 2 minutes of amino acid addition and peaks by 5 minutes, in step with leucine arriving in lysosomes; phosphorylation of classic mTORC1 targets lags behind, suggesting mTORC1 passes briefly through the lysosome before acting on substrates elsewhere. |
| 2015 | M | Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway SAX2015 Solves the crystal structure of Sestrin2 bound to leucine, revealing the molecular pocket that lets it act as mTORC1's dedicated leucine sensor. |
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