Cholesterol
A membrane sterol that mTORC1 treats as a nutrient input, read at the lysosome rather than at the cell surface. Two routes into the same machinery are described: cholesterol binds the permease-like region of LYCHOS, which then sequesters GATOR1 (SHI2022), and it acts through SLC38A9 independently of that transporter's arginine-sensing function, with NPC1 restraining the signal as it exports cholesterol from the lumen (CAS2017). Both rest on human cell lines and biochemistry. How the two routes divide the signal, and whether either matters at the level of an organism, is not measured in this corpus.
A building block the cell counts before it grows. Cholesterol is a fat the cell needs as a building material for its membranes, so it makes sense that the cell checks how much it has before deciding to grow. The checking happens at the lysosome, the recycling compartment, not at the cell's outer surface. There are two known ways the message gets through, and nobody has measured how much of the work each one does.
Two routes are described into the same machinery: cholesterol binds the permease-like region of LYCHOS, which then sequesters GATOR1 (SHI2022), and it acts through SLC38A9 independently of that transporter's arginine-sensing function, with NPC1 restraining the signal as it exports sterol from the lumen (CAS2017). Both rest on human cell lines and biochemistry; how the two divide the signal is not measured here. Drawn on the input band with the amino acids because it is a nutrient the cell counts -- the sensing step itself happens in the lysosomal lumen.
TL;DR. Cholesterol appears in 3 curated studies in Oliver's mTOR Atlas: 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 |
|---|---|---|---|
| Cholesterol activates LYCHOS (GPR155) mechanism: binding · this link in full · on the map table | Cholesterol itself sticks to the sensor. That is what tells the sensor there is plenty about: break the spot where it sticks and the growth signal no longer goes through, even though the sensor is still there. The reading is taken at the lysosome, where cholesterol arrives, not at the outside of the cell. Holds under: Single-study edge in this corpus (SHI2022): human cell lines, photoaffinity and mutational biochemistry. The binding site was later resolved by cryo-EM outside this corpus (Bayly-Jones 2024, PMID 39358511; Zhao 2025, PMID 39824976; Li 2025, PMID 41058362). What is shown is that occupancy of the site is required for cholesterol-driven mTORC1 activation in cultured cells; no dose-response in tissue, no animal or human endpoint, and no measurement of how this route divides the signal with the SLC38A9-NPC1 complex (CAS2017). plausible in people, not shown directly · emerging, few independent studies | M | SHI2022 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| 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 |
|---|---|---|
| 2022 | M | Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1 SHI2022 Identifies LYCHOS (previously annotated GPR155) as a lysosomal cholesterol sensor for mTORC1. Cholesterol binds the amino-terminal permease-like region; mutating that site impairs mTORC1 activation. At high cholesterol LYCHOS binds GATOR1 through a conserved cytoplasm-facing loop, and by sequestering GATOR1 it promotes cholesterol- and Rag-dependent recruitment of mTORC1 to the lysosome. Boundary: human cell lines and biochemistry, not an organismal phenotype. |
| 2017 | M | Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex CAS2017 Establishes lysosomal cholesterol as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface. SLC38A9 is required for cholesterol-driven mTORC1 activation through conserved cholesterol-responsive motifs, and does so independently of its arginine-sensing function; NPC1, which exports cholesterol from the lysosome, binds SLC38A9 and restrains mTORC1 through its sterol transport function. Boundary: cell lines and patient-derived fibroblasts, no organismal endpoint. |
| 2013 | M | Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity KID2013 Activating T cells switch on cholesterol and fatty acid synthesis genes within hours, and this paper showed the switch runs through PI3K and mTOR to SREBP: 100 nM rapamycin given 30 minutes before stimulation blocked the induction of the lipogenic programme, prevented processing of full-length SREBP and its accumulation in the nucleus, and reduced SREBP1 and SREBP2 occupancy at lipogenic promoters to background. Deleting Scap in T cells, which removes both SREBP1 and SREBP2 activity, left thymic and peripheral T-cell numbers normal but the cells could not blast: they entered G1 and stalled, failed to raise cholesterol and fatty acids after activation, and increased ECAR and OCR only modestly where controls rose about ten-fold and four-fold. Adding cholesterol conjugated to methyl-beta-cyclodextrin roughly doubled survival at 48 hours (21 to 45 percent) and restored growth, cell-cycle entry and ER expansion, which points to cholesterol as the limiting step. After LCMV-Armstrong infection the Scap-deficient mice had fewer virus-specific CD8 T cells with lower IFN-gamma and TNF, while homeostatic proliferation was unaffected. Boundary: mouse genetics and mouse cells; the mTOR step is shown with rapamycin pretreatment in cultured T cells, and the in vivo arm measures the consequence of losing SREBP activity rather than of inhibiting mTOR. |
Related entities
Thank you. Your answer was counted anonymously.