Nahum Sonenberg
Discovered the ordered two-step phosphorylation mechanism by which mTOR-regulated 4E-BP1 controls cap-dependent translation
BSc & MSc in microbiology and immunology, Tel Aviv University · PhD, Weizmann Institute of Science (1976) · postdoc, Roche Institute of Molecular Biology (Aaron Shatkin lab) · joined McGill University (1979) · now James McGill Professor of Biochemistry and Gilman Cheney Chair, McGill University; Director, Rosalind and Morris Goodman Cancer Research Centre
Faculty profile, 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 directs the Rosalind and Morris Goodman Cancer Research Centre.
Milestones in the Atlas
| 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. |
| 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. |