Integrated stress response
Conserved response to unfolded protein, amino-acid and other stresses. Reaches mTORC1 by more than one route: ATF4-induced REDD1 acts through the TSC complex, while ATF4-induced Sestrin2 acts on GATOR2. It is not a single brake, and it is not the AMPK one.
The cell's alarm for damaged protein-making. The cell's general-purpose alarm system for problems like misfolded proteins or amino-acid shortage. It suppresses mTORC1 by more than one route: one of them (REDD1) works through the TSC brake, another (Sestrin2) works on GATOR2. So it is not one single brake, and it is not the AMPK one.
ATF4 is the shared node: mTORC1 drives ATF4 translation, and ISR activation drives ATF4 independently, so the two systems are cross-wired rather than serial.
TL;DR. Integrated stress response appears in 4 curated studies in Oliver's mTOR Atlas: 1 in animal models; 3 at the molecular level (cells, biochemistry, structure). No study in people is recorded for it in the Atlas yet. It has 1 interaction in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| Integrated stress response activates Spalt-related (Salr) mechanism: transcriptional · this link in full · on the map table | The cell's stress-response system switches on a growth-blocking gene – a route to shutting down mTORC1 that skips right past TSC and AMPK. The integrated stress response switches on Salr, a growth inhibitor - a route into mTORC1 that bypasses TSC and AMPK entirely. The integrated stress response switches on Salr, a growth inhibitor - a route into mTORC1 that bypasses TSC and AMPK entirely. Holds under: Fly only, and newly reported. not tested in people · emerging, few independent studies | A | DEN2026 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| A | Animal model | 1 |
| M | Molecular — cells, biochemistry, structure | 3 |
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 | Spalt-related is an inhibitor of mTORC1-mediated growth activated by the integrated stress response DEN2026 Transcription factor Spalt-related (Salr) is a novel mTORC1 inhibitor in Drosophila activated by the integrated stress response, restricting anabolic growth and lipid storage during nutrient stress. Salr responds to a distinct, ISR-driven cue, acting convergently with FoxO rather than downstream of it. |
| 2026 | M | Amino acid homeostasis by CORVET/HOPS: A metabolic and stress resilience checkpoint for T cells WANG2026 Identifies the CORVET and HOPS endolysosomal tethering complexes as upstream suppliers of intracellular amino acids in activated T cells, acquired via macropinocytosis. Loss of the core subunits VPS18 or VPS11 starves the cell of amino acids, switches on the integrated stress response and shuts down mTORC1; enforced mTORC1 activity rescues the proliferative defect while BIM deletion rescues survival, separating the two failure modes. Places vesicular nutrient acquisition upstream of the canonical lysosomal amino-acid-sensing arm of mTORC1. |
| 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. |
| 2026 | M | Mathematical Modeling of Dietary Timing- and Protein Quality-Responsive Liver Circadian Clock and its Function on Ribosome Biogenesis LU2026 Builds a semi-mechanistic model in which liver mTORC1 and GCN2-ISR signalling are driven by RHYTHMS in dietary essential amino acid availability rather than by a fixed nutrient level. Simulations show the two pathways jointly set metabolic entrainability and are required to keep the peripheral clock and ribosome biogenesis synchronised under nutrient stress, and predict individualised recovery trajectories after a transient dietary disruption. A worked example of treating mTORC1 activity as a time-varying pattern whose shape — not just its average — determines the downstream growth output. |
Related entities
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