Nahum Sonenberg
Co-discovered the mRNA cap-binding protein eIF4E and the 4E-BP proteins that restrain it, and showed how mTOR releases this brake to control protein synthesis
Distinguished James McGill Professor of Biochemistry and Gilman Cheney Chair, McGill University; member, Rosalind and Morris Goodman Cancer Institute · joined McGill University (1979) · postdoc, Roche Institute of Molecular Biology (Aaron Shatkin lab) · PhD, Weizmann Institute of Science (1976) · BSc & MSc in microbiology and immunology, Tel Aviv University
Faculty profile, McGill University (Montreal, Quebec, Canada) ↗ Lab lineagetrained under Aaron J. Shatkin →
Portrait: Goodman Cancer Institute, McGill University
In 1999, Sonenberg's group worked out how the translational repressor 4E-BP1 is actually switched off: rather than being phosphorylated all at once, it is modified through an ordered, priming two-step mechanism, in which phosphorylation at certain sites must occur before others can follow, and only the fully phosphorylated protein releases its grip on the cap-binding protein eIF4E. Since eIF4E is the factor that recognizes the 5' cap of mRNA and recruits it into the ribosome, this phosphorylation cascade — which sits downstream of mTORC1 — acts as a molecular switch that turns on cap-dependent protein synthesis when nutrients and growth signals are abundant. In 2013, his lab extended this logic to metabolism, showing that mTORC1, acting specifically through 4E-BP-dependent control of translation, regulates the biogenesis and activity of mitochondria.
Sonenberg did his PhD at the Weizmann Institute of Science and then a postdoctoral fellowship with Aaron Shatkin at the Roche Institute of Molecular Biology, where the two identified eIF4E, the protein that binds the 5' cap of messenger RNA — the discovery that set the direction for his entire career studying translational control. He joined McGill University's Department of Biochemistry in 1979 and has remained there since.
Sonenberg is a Fellow of the Royal Society, an Officer of the Order of Canada, and a Foreign Associate of the US National Academy of Sciences; his honors include the Gairdner Foundation International Award and the Wolf Prize in Medicine. He currently holds the Gilman Cheney Chair in Biochemistry at McGill and is a member of the Rosalind and Morris Goodman Cancer Institute.
Milestones in the Atlas
A selection, not a full bibliography: only papers that meet the Atlas inclusion criteria.
| Year | Evidence | Study |
|---|---|---|
| 1999 | M | Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism GIN1999 Shows that 4E-BP1 phosphorylation follows an ordered, priming two-step mechanism that determines when 4E-BP1 releases eIF4E to permit cap-dependent translation. |
| 2002 | M | A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus TAN2002 Co-author: mTOR, the 4E-BPs and eIF4E sit in hippocampal dendrites near synapses, and rapamycin reduced late-phase LTP and BDNF-induced potentiation in rodent hippocampal slices. |
| 2009 | R | Translational control of long-lasting synaptic plasticity and memory COS2009 Senior author of a narrative review on how the mTORC1 and eIF2alpha pathways control the start of translation in long-lasting synaptic plasticity and long-term memory. |
| 2012 | M | Distinct perturbation of the translatome by the antidiabetic drug metformin LAR2012 Senior author: shows metformin reshapes the translatome in cancer cells through mTORC1 and 4E-BPs, selectively lowering translation of cell-cycle mRNAs. |
| 2013 | A | Autism-related deficits via dysregulated eIF4E-dependent translational control GKO2013 Senior author: mice lacking 4E-BP2 showed autism-like behaviours with increased translation of neuroligin mRNAs, and blocking eIF4E reversed the social deficit. |
| 2013 | M | mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation MOR2013 Shows that mTORC1 controls mitochondrial biogenesis and activity specifically through 4E-BP-dependent regulation of translation. |
Co-authors in the Atlas 11
People with a profile here who share at least one study with Nahum Sonenberg.
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- Anne-Claude Gingras 2 shared studies Showed in 1999 that mTOR phosphorylates 4E-BP1 in a priming two-step mechanism, and now leads work on interaction proteomics (including BioID) that maps how cells read signals such as mTORC1
- Davide Ruggero Showed that oncogenic mTOR signalling reprograms which mRNAs are translated, and that tumours become addicted to this through the 4E-BP–eIF4E axis. His UCSF lab found that mTOR-driven translation of a specific set of mRNAs promotes prostate cancer invasion and metastasis
- Erin M. Schuman Studies how neurons make and break down proteins locally in dendrites and axons; her group helped tie a rapamycin-sensitive mTOR pathway to the protein-synthesis-dependent phase of synaptic plasticity.
- Christos G. Gkogkas Studies how protein synthesis is controlled in the brain; first author of the mouse study linking loss of the translational repressor 4E-BP2, downstream of mTORC1, to autism-like behaviour through increased neuroligin translation.
- Julie St-Pierre Biochemist and Vice-President, Research and Innovation at the University of Ottawa who studies how cancer cells adapt their metabolism, and a co-author on McGill work linking mTORC1 to mitochondria and to rapamycin-induced fatty liver
- Masahiro Morita Biochemist at UT Health San Antonio who studies how mTORC1 controls protein synthesis, mRNA decay and mitochondria, and how these links go wrong in cancer and metabolic disease
- Mauro Costa-Mattioli Neuroscientist who studies how mTOR signaling and protein synthesis control learning, memory and brain function, including the role of mTORC2 in long-term memory.
- Ola Larsson Studies how mRNA translation is altered in cancer and develops methods to measure genome-wide translation; helped show that metformin changes which mRNAs cancer cells translate, through the mTORC1/4E-BP pathway.
- Robert T. Abraham Co-discovered the mammalian target of rapamycin in 1995, giving it the name mTOR, and showed that it directly phosphorylates the translation repressor 4E-BP1 (PHAS-I)
- Shao-Jun Tang Neuroscientist who, as a postdoc in Erin Schuman's group at Caltech, helped show that a rapamycin-sensitive mTOR pathway is needed for the protein-synthesis-dependent late phase of hippocampal LTP; his lab now studies chronic pain.
- 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
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