Rachel L. Wolfson
Identified Sestrin2 as the direct leucine sensor of the mTORC1 pathway as a Sabatini-lab MD-PhD student. She also co-discovered KICSTOR, the complex that recruits GATOR1 to the lysosome
Assistant Professor of Cell Biology, Harvard Medical School · postdoc, Department of Neurobiology, Harvard Medical School · clinical training, Massachusetts General Hospital · MD, Harvard Medical School; PhD, MIT (Sabatini lab)
Wolfson Lab, Harvard Medical School (Boston, Massachusetts, USA) ↗ Lab lineagetrained under David M. Sabatini → ORCID0000-0003-3873-829X ↗
Portrait: Harvard Medical School, Dept. of Cell Biology
As an MD-PhD student in David Sabatini's lab, Rachel Wolfson identified Sestrin2 as a direct biochemical sensor for the amino acid leucine: when leucine binds Sestrin2, it is released from the GATOR2 complex, relieving a brake on mTORC1 and switching growth signalling on. It answered a question the field had chased for years — how a single amino acid's concentration gets converted into a growth signal.
Wolfson went on to identify KICSTOR, a complex that recruits GATOR1 to the lysosome and is required for amino-acid or glucose deprivation to inhibit mTORC1, completing another structural piece of the pathway. She later trained in neurobiology and joined the Harvard Medical School faculty in 2024, where her lab now studies how sensory neurons detect signals from internal organs.
The timeline below follows her contributions gathered in this Atlas.
Milestones in the Atlas
A selection, not a full bibliography: only papers that meet the Atlas inclusion criteria.
| Year | Evidence | Study |
|---|---|---|
| 2012 | A | Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival EFE2012 Rag-GTPase control of mTORC1 is essential for neonatal autophagy and survival to fasting. |
| 2014 | M | The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1 CHA2014 Sestrins bind GATOR2 to negatively regulate amino-acid signalling upstream of mTORC1. |
| 2015 | M | Sestrin2 is a leucine sensor for the mTORC1 pathway WOL2015 Identifies Sestrin2 as a direct leucine sensor for the mTORC1 pathway. |
| 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. |
| 2015 | M | Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1 WAN2015 The lysosomal transporter SLC38A9 signals arginine sufficiency to mTORC1. |
| 2017 | M | KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1 WOL2017 Identifies KICSTOR, the complex that recruits GATOR1 to the lysosome and is required for nutrient signalling to mTORC1. |
| 2017 | M | mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient WYA2017 SLC38A9 effluxes essential amino acids (e.g. leucine) from lysosomes to activate mTORC1. |
| 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. |
Co-authors in the Atlas 25
People with a profile here who share at least one study with Rachel L. Wolfson.
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- David M. Sabatini 8 shared studies Identified mTOR (as RAFT1) in 1994. His lab then mapped much of the machinery around it: raptor and rictor at the core of mTORC1 and mTORC2, the Rag–Ragulator system that docks mTORC1 on the lysosome, and the sensors that detect leucine, arginine and SAM
- Lynne Chantranupong 5 shared studies Showed as a Sabatini-lab graduate student that the Sestrins act through GATOR2 to regulate amino-acid signalling to mTORC1. She then discovered the CASTOR proteins, the cell's arginine sensors for the pathway
- Gregory A. Wyant 3 shared studies Showed that the lysosomal protein SLC38A9 exports leucine and other essential amino acids out of the lysosome, letting cells grow on proteins they have taken up and broken down there
- Kuang Shen 3 shared studies Solved, as a Sabatini-lab postdoc, cryo-EM structures of GATOR1 and of the FLCN–FNIP2–Rag–Ragulator complex, two switches that set mTORC1 activity. His UMass Chan lab studies the structural basis of nutrient sensing
- Robert A. Saxton 3 shared studies Solved, as a Sabatini-lab graduate student, the structures of the leucine sensor Sestrin2 and the arginine sensor CASTOR1, showing how each one grips its amino acid. He also co-wrote a widely cited 2017 review of mTOR signalling with David Sabatini
- Sonia M. Scaria 3 shared studies Contributed, as an MIT undergraduate in the Sabatini lab, to the discovery of CASTOR1 as the arginine sensor and SAMTOR as the SAM sensor of the mTORC1 pathway
- Jose M. Orozco 2 shared studies Researcher trained in David Sabatini's laboratory at the Whitehead Institute and MIT who showed that mTORC1 senses glucose through the glycolysis metabolite DHAP
- Liron Bar-Peled 2 shared studies Showed as a Sabatini-lab graduate student that Ragulator switches the Rag GTPases on, acting as their GEF. He also discovered GATOR1 and GATOR2; GATOR1 switches the Rags off and its genes are mutated in some cancers
- Monther Abu-Remaileh 2 shared studies Worked out how to isolate lysosomes fast enough to measure what is inside them, and found that mTOR controls what gets out
- Roberto Zoncu 2 shared studies Showed as a postdoc that mTORC1 senses amino acids from inside the lysosome, through the v-ATPase and Ragulator. His Berkeley lab has since mapped how the Rag GTPases and the folliculin complex switch mTORC1 on, and how lysosomal cholesterol feeds into the same system
- Tim Wang 2 shared studies Co-developed genome-wide CRISPR screening in human cells (reported in parallel by Feng Zhang's lab) as a graduate student with David Sabatini and Eric Lander, and contributed to studies showing that the 4E-BPs mediate mTORC1's control of translation and that CASTOR1 senses arginine
- Alejo Efeyan Showed that the Rag GTPases, which relay amino-acid signals to mTORC1, are a life-or-death switch for newborn mice surviving the fast before their first feeding
- Elizabeth D. Yuan Second author on the study showing that S6K1 phosphorylates BMAL1 to link mTOR signalling with circadian protein synthesis, and co-author on the follow-up in tuberous sclerosis models.
- Elizaveta Freinkman Chemist and mass-spectrometry specialist at the Whitehead Institute who measured metabolites for many studies of nutrient sensing and cancer metabolism, including the lysosome amino acid work behind two Atlas papers
- Eric Spooner Manager of the Whitehead Institute's Proteomics Core Facility, whose mass spectrometry work identified proteins in complexes for many Whitehead studies, including two on amino acid sensing upstream of mTORC1
- Choah Kim Researcher in David Sabatini's lab at the Whitehead Institute who contributed to three studies on how amino acids at the lysosome are sensed by mTORC1
- Kendall J. Condon Ran genome-wide CRISPR screens revealing how mitochondrial stress signals to mTORC1
- Kevin E. Knockenhauer Structural biologist trained in Thomas Schwartz's MIT lab who helped solve the amino acid sensor structures of Sestrin2 and CASTOR1, and who later moved to drug discovery at Accent Therapeutics
- Michael E. Pacold Radiation oncologist and chemical biologist at NYU Langone who studies the metabolism of brain tumours, and a co-author of the Sabatini lab's structure of the leucine sensor Sestrin2
- Shuyu Wang Co-discovered SLC38A9 as a Sabatini-lab MD-PhD student, a lysosomal amino-acid transporter that signals arginine sufficiency to mTORC1
- Steven P. Gygi Mass-spectrometry scientist whose Harvard lab builds large-scale proteomics methods, including the BioPlex human protein-interaction map, and contributed proteomics to the discoveries of the CASTOR and SAMTOR nutrient sensors
- Thomas U. Schwartz MIT structural biologist who studies how molecules pass across the nuclear envelope, and whose crystallography lab helped solve the leucine and arginine sensor structures upstream of mTORC1
- Walter W. Chen Co-author of the 2017 Cell paper showing that SLC38A9 releases essential amino acids from lysosomes to switch on mTORC1
- Xin Gu Cell biologist who discovered SAMTOR, the sensor that lets mTORC1 read the methyl donor SAM, as a PhD student at MIT, and who now leads a lab at Dana-Farber and Harvard Medical School studying ubiquitin-independent protein destruction by the midnolin-proteasome pathway
- Zhi-Yang Tsun Biologist who, as first author in David Sabatini's lab, showed that the tumour suppressor folliculin is a GAP for the RagC and RagD GTPases that carry the amino acid signal to mTORC1
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