Known as much for its complexity as its vital role in regulating cellular and organismal growth, the mechanistic target of rapamycin complex 1 (mTORC1) pathway has seemingly been acting in mysterious ways.
Through a variety of mechanistic interactions, mTORC1 interprets cues in the cellular environment, including the availability of nutrients, and signals the organism to act accordingly. mTORC1 is apt to trigger growth during times of abundance and dial back metabolism when food is scarce.
Owing to years of intense scrutiny in the lab of Whitehead Institute Member David Sabatini, the key players of this pathway—whose deregulation is associated with diseases ranging from diabetes to cancer to epilepsy—have gradually been brought to light. Yet, one essential question remained unanswered: How exactly does mTORC1 actually detect the presence of nutrients?
Now, it seems, scientists in Sabatini’s lab have at least a partial answer, describing for the first time a protein that appears to sense the amino acid arginine. The discovery of this transmembrane protein, known as SLC38A9, is reported this week in the journal Science.
“No one doubts that this is an important pathway, with implications for aging, cancer, and diabetes, and we had figured out the core machinery of the pathway,” says Sabatini. “But the mystery has been what are the sensors? Now we’ve found what is likely the first nutrient sensor. This is what connects that core machinery to the world around it.”
The finding suggests a model in which mTORC1, located at the surface of cellular components known as lysosomes, receives “go/no-go” signals from a family of enzymes dubbed Rag GTPases. It had been known that the Rags convey information about nutritional status to mTORC1, but it wasn’t clear how the Rags came by this information. Through a series of experiments, researchers found that SLC38A9 is capable of transporting and directly interacting with amino acids, the building blocks of proteins.
Further, they found that in cells overexpressing SLC38A9, mTORC1 signaling is activated even in the absence of amino acids. On the flipside, they found mTORC1 activation defective in cells engineered to lack expression of SLC38A9. Taken together, such compelling evidence points to SLC38A9 as an amino acid sensor, tipping off the Rags to the availability of nutrients.
“It’s like a relay race and this protein is what starts the race,” says Zhi-Yang Tsun, a graduate student in Sabatini’s lab and co-first author of the Science paper. “We’ve been looking for a long time for a molecule like this. It has all the properties consistent with a sensor.”
As new components of the pathway are identified and their roles elucidated, the number of potential targets that could be manipulated therapeutically increases. Historically, drug development activities in this space have focused on blocking mTORC1 activation, in part because hyperactivation of the pathway can lead to aberrant growth seen in cancer or metabolic abnormalities associated with diabetes. Intriguingly, because SLC38A9 activates the pathway, it may represent a target for clinical situations in which growth stimulation is desirable.
“It would be interesting to have to have small molecular handles to perturb the pathway, turning it on or off,” says Shuyu Wang, another Sabatini lab graduate student and co-first author of the Science paper. “In this case, one could think about situations where you would want to increase protein synthesis, perhaps to treat muscle atrophy and disease-related weight loss.”
Although the discovery of the first nutrient sensor in this pathway represents an important advance, the researchers know much work lies ahead. SLC38A9’s specificity for arginine suggests that many more such sensors—for other amino acids and glucose, for example—interact either directly or indirectly with mTORC1. Identifying them will thus remain a focus of the lab for years to come.
This work was supported by the National Institutes of Health (grants R01 CA103866 and AI47389), the United States Department of Defense (grant W81XWH-07-0448), the Howard Hughes Medical Institute, a National Defense Science and Engineering Fellowship, a National Science Foundation Graduate Research Fellowship, an American Cancer Society - Ellison Foundation Postdoctoral Fellowship, and a German Academic Exchange Service/DAAD Fellowship.
Written by Matt Fearer
* * *
David Sabatini's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.
* * *
“Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1”
Science, January 7, 2015
Shuyu Wang (1,2,3,4), Zhi-Yang Tsun (1,2,3,4), Rachel Wolfson (1,2,3,4), Kuang Shen (1,2,3,4), Gregory A. Wyant (1,2,3,4), Molly E. Plovanich (6), Elizabeth D. Yuan (1,2,3,4), Tony D. Jones (1,2,3,4), Lynne Chantranupong (1,2,3,4), William Comb (1,2,3,4), Tim Wang (1,2,3,4), Liron Bar-Peled (1,2,3,4)*, Roberto Zoncu (1,2,3,4)**, Christoph Straub (5), Choah Kim (1,2,3,4), Jiwon Park (1,2,3,4), Bernardo L. Sabatini (5), and David M. Sabatini (1,2,3,4)
1. Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA.
2. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
4. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA.
5. Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
6. Harvard Medical School, 260 Longwood Avenue, Boston, MA 02115, USA.
* Present address: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
** Present address: Department of Molecular and Cell Biology, University of California
Berkeley, Berkeley, CA 94720, USA
Matt Fearer | newswise
Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory
How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy