Full Text Journal Articles by
Author David M. Sabatini


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Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction.

Kendall J Condon, Jose M Orozco, Charles H Adelmann, Jessica B Spinelli, Pim W van der Helm, Justin M Roberts, Tenzin Kunchok, David M Sabatini,

In mammalian cells, nutrients and growth factors signal through an array of upstream proteins to regulate the mTORC1 growth control pathway. Because the full complement of these proteins has not been systematically identified, we developed a FACS-based CRISPR-Cas9 genetic screening strategy to pinpoint genes that regulate mTORC1 activity. Along with ... Read more >>

Proc Natl Acad Sci U S A (Proceedings of the National Academy of Sciences of the United States of America)
[2021, 118(4):]

Cited: 7 times

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MCART1/SLC25A51 is required for mitochondrial NAD transport.

Nora Kory, Jelmi Uit de Bos, Sanne van der Rijt, Nevena Jankovic, Miriam Güra, Nicholas Arp, Izabella A Pena, Gyan Prakash, Sze Ham Chan, Tenzin Kunchok, Caroline A Lewis, David M Sabatini,

The nicotinamide adenine dinucleotide (NAD<sup>+</sup>/NADH) pair is a cofactor in redox reactions and is particularly critical in mitochondria as it connects substrate oxidation by the tricarboxylic acid (TCA) cycle to adenosine triphosphate generation by the electron transport chain (ETC) and oxidative phosphorylation. While a mitochondrial NAD<sup>+</sup> transporter has been identified ... Read more >>

Sci Adv (Science advances)
[2020, 6(43):]

Cited: 12 times

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ATRAID regulates the action of nitrogen-containing bisphosphonates on bone.

Lauren E Surface, Damon T Burrow, Jinmei Li, Jiwoong Park, Sandeep Kumar, Cheng Lyu, Niki Song, Zhou Yu, Abbhirami Rajagopal, Yangjin Bae, Brendan H Lee, Steven Mumm, Charles C Gu, Jonathan C Baker, Mahshid Mohseni, Melissa Sum, Margaret Huskey, Shenghui Duan, Vinieth N Bijanki, Roberto Civitelli, Michael J Gardner, Chris M McAndrew, William M Ricci, Christina A Gurnett, Kathryn Diemer, Fei Wan, Christina L Costantino, Kristen M Shannon, Noopur Raje, Thomas B Dodson, Daniel A Haber, Jan E Carette, Malini Varadarajan, Thijn R Brummelkamp, Kivanc Birsoy, David M Sabatini, Gabe Haller, Timothy R Peterson,

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFF) and osteonecrosis of ... Read more >>

Sci Transl Med (Science translational medicine)
[2020, 12(544):]

Cited: 3 times

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A PEROXO-Tag Enables Rapid Isolation of Peroxisomes from Human Cells.

G Jordan Ray, Elizabeth A Boydston, Emily Shortt, Gregory A Wyant, Sebastian Lourido, Walter W Chen, David M Sabatini,

Peroxisomes are metabolic organelles that perform a diverse array of critical functions in human physiology. Traditional isolation methods for peroxisomes can take more than 1 h to complete and can be laborious to implement. To address this, we have now extended our prior work on rapid organellar isolation to peroxisomes via ... Read more >>

iScience (iScience)
[2020, 23(5):101109]

Cited: 5 times

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Correction for: Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance.

Lan Ye, Anne L Widlund, Carrie A Sims, Dudley W Lamming, Yuxia Guan, James G Davis, David M Sabatini, David E Harrison, Ole Vang, Joseph A Baur,

Aging (Albany NY) (Aging)
[2020, 12(7):6486-6487]

Cited: 0 times

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Correction: An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1.

Carson C Thoreen, Seong A Kang, Jae Won Chang, Qingsong Liu, Jianming Zhang, Yi Gao, Laurie J Reichling, Taebo Sim, David M Sabatini, Nathanael S Gray,

J Biol Chem (The Journal of biological chemistry)
[2020, 295(9):2886]

Cited: 1 time

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mTOR at the nexus of nutrition, growth, ageing and disease.

Grace Y Liu, David M Sabatini,

The mTOR pathway integrates a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic cell growth. Over the past two and a half decades, mapping of the mTOR signalling landscape has revealed that mTOR controls biomass accumulation and metabolism by modulating key cellular ... Read more >>

Nat Rev Mol Cell Biol (Nature reviews. Molecular cell biology)
[2020, 21(4):183-203]

Cited: 196 times

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Author Correction: A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance.

Raghu R Chivukula, Daniel T Montoro, Hui Min Leung, Jason Yang, Hanan E Shamseldin, Martin S Taylor, Gerard W Dougherty, Maimoona A Zariwala, Johnny Carson, M Leigh Anne Daniels, Patrick R Sears, Katharine E Black, Lida P Hariri, Ibrahim Almogarri, Evgeni M Frenkel, Vladimir Vinarsky, Heymut Omran, Michael R Knowles, Guillermo J Tearney, Fowzan S Alkuraya, David M Sabatini,

An amendment to this paper has been published and can be accessed via a link at the top of the paper. ... Read more >>

Nat Med (Nature medicine)
[2020, 26(2):300]

Cited: 2 times

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Nutrient mTORC1 signaling underpins regulatory T cell control of immune tolerance.

Mytrang H Do, Xinxin Wang, Xian Zhang, Chun Chou, Briana G Nixon, Kristelle J Capistrano, Min Peng, Alejo Efeyan, David M Sabatini, Ming O Li,

Foxp3+ regulatory T (T reg) cells are pivotal regulators of immune tolerance, with T cell receptor (TCR)-driven activated T reg (aT reg) cells playing a central role; yet how TCR signaling propagates to control aT reg cell responses remains poorly understood. Here we show that TCR signaling induces expression of ... Read more >>

J Exp Med (The Journal of experimental medicine)
[2020, 217(1):]

Cited: 11 times

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Nutrient regulation of mTORC1 at a glance.

Kendall J Condon, David M Sabatini,

The mechanistic target of rapamycin (mTOR) signaling pathway coordinates environmental and intracellular cues to control eukaryotic cell growth. As a pivot point between anabolic and catabolic processes, mTOR complex 1 (mTORC1) signaling has established roles in regulating metabolism, translation and autophagy. Hyperactivity of the mTOR pathway is associated with numerous ... Read more >>

J Cell Sci (Journal of cell science)
[2019, 132(21):]

Cited: 41 times

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Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium.

Nalle Pentinmikko, Sharif Iqbal, Miyeko Mana, Simon Andersson, Armand B Cognetta, Radu M Suciu, Jatin Roper, Kalle Luopajärvi, Eino Markelin, Swetha Gopalakrishnan, Olli-Pekka Smolander, Santiago Naranjo, Tuure Saarinen, Anne Juuti, Kirsi Pietiläinen, Petri Auvinen, Ari Ristimäki, Nitin Gupta, Tuomas Tammela, Tyler Jacks, David M Sabatini, Benjamin F Cravatt, Ömer H Yilmaz, Pekka Katajisto,

A decline in stem cell function impairs tissue regeneration during ageing, but the role of the stem-cell-supporting niche in ageing is not well understood. The small intestine is maintained by actively cycling intestinal stem cells that are regulated by the Paneth cell niche<sup>1,2</sup>. Here we show that the regenerative potential ... Read more >>

Nature (Nature)
[2019, 571(7765):398-402]

Cited: 36 times

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Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program.

Chintan K Kikani, Xiaoying Wu, Sarah Fogarty, Seong Anthony Woo Kang, Noah Dephoure, Steven P Gygi, David M Sabatini, Jared Rutter,

During skeletal muscle regeneration, muscle stem cells (MuSCs) respond to multiple signaling inputs that converge onto mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. mTOR function is essential for establishment of the differentiation-committed progenitors (early stage of differentiation, marked by the induction of <i>myogenin</i> expression), myotube fusion, and, ultimately, ... Read more >>

Proc Natl Acad Sci U S A (Proceedings of the National Academy of Sciences of the United States of America)
[2019, 116(21):10382-10391]

Cited: 8 times

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Arg-78 of Nprl2 catalyzes GATOR1-stimulated GTP hydrolysis by the Rag GTPases.

Kuang Shen, Max L Valenstein, Xin Gu, David M Sabatini,

mTOR complex 1 (mTORC1) is a major regulator of cell growth and proliferation that coordinates nutrient inputs with anabolic and catabolic processes. Amino acid signals are transmitted to mTORC1 through the Rag GTPases, which directly recruit mTORC1 onto the lysosomal surface, its site of activation. The Rag GTPase heterodimer has ... Read more >>

J Biol Chem (The Journal of biological chemistry)
[2019, 294(8):2970-2975]

Cited: 13 times

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SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism.

Nora Kory, Gregory A Wyant, Gyan Prakash, Jelmi Uit de Bos, Francesca Bottanelli, Michael E Pacold, Sze Ham Chan, Caroline A Lewis, Tim Wang, Heather R Keys, Yang Eric Guo, David M Sabatini,

One-carbon metabolism generates the one-carbon units required to synthesize many critical metabolites, including nucleotides. The pathway has cytosolic and mitochondrial branches, and a key step is the entry, through an unknown mechanism, of serine into mitochondria, where it is converted into glycine and formate. In a CRISPR-based genetic screen in ... Read more >>

Science (Science (New York, N.Y.))
[2018, 362(6416):]

Cited: 49 times

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Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms.

Kuang Shen, David M Sabatini,

The mechanistic target of rapamycin complex 1 (mTORC1) growth pathway detects nutrients through a variety of sensors and regulators that converge on the Rag GTPases, which form heterodimers consisting of RagA or RagB tightly bound to RagC or RagD and control the subcellular localization of mTORC1. The Rag heterodimer uses ... Read more >>

Proc Natl Acad Sci U S A (Proceedings of the National Academy of Sciences of the United States of America)
[2018, 115(38):9545-9550]

Cited: 40 times

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DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation.

Johannes Wedel, Sarah Bruneau, Kaifeng Liu, Sek Won Kong, Peter T Sage, David M Sabatini, Mathieu Laplante, David M Briscoe,

DEPTOR is an evolutionarily conserved cell-intrinsic binding partner of mTOR that functions as a negative regulator of signaling responses. In this study, we show that DEPTOR is expressed within CD4<sup>+</sup> T cells, and we observed that its relative level of expression modulates differentiation as well as glucose utilization within CD4<sup>+</sup> ... Read more >>

Am J Transplant (American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons)
[2019, 19(1):77-88]

Cited: 4 times

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NUFIP1 is a ribosome receptor for starvation-induced ribophagy.

Gregory A Wyant, Monther Abu-Remaileh, Evgeni M Frenkel, Nouf N Laqtom, Vimisha Dharamdasani, Caroline A Lewis, Sze Ham Chan, Ivonne Heinze, Alessandro Ori, David M Sabatini,

The lysosome degrades and recycles macromolecules, signals to the master growth regulator mTORC1 [mechanistic target of rapamycin (mTOR) complex 1], and is associated with human disease. We performed quantitative proteomic analyses of rapidly isolated lysosomes and found that nutrient levels and mTOR dynamically modulate the lysosomal proteome. Upon mTORC1 inhibition, ... Read more >>

Science (Science (New York, N.Y.))
[2018, 360(6390):751-758]

Cited: 92 times

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Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors.

Jason M Rohde, Kyle R Brimacombe, Li Liu, Michael E Pacold, Adam Yasgar, Dorian M Cheff, Tobie D Lee, Ganesha Rai, Bolormaa Baljinnyam, Zhuyin Li, Anton Simeonov, Matthew D Hall, Min Shen, David M Sabatini, Matthew B Boxer,

Proliferating cells, including cancer cells, obtain serine both exogenously and via the metabolism of glucose. By catalyzing the first, rate-limiting step in the synthesis of serine from glucose, phosphoglycerate dehydrogenase (PHGDH) controls flux through the biosynthetic pathway for this important amino acid and represents a putative target in oncology. To ... Read more >>

Bioorg Med Chem (Bioorganic & medicinal chemistry)
[2018, 26(8):1727-1739]

Cited: 9 times

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A mouse model of DEPDC5-related epilepsy: Neuronal loss of Depdc5 causes dysplastic and ectopic neurons, increased mTOR signaling, and seizure susceptibility.

Christopher J Yuskaitis, Brandon M Jones, Rachel L Wolfson, Chloe E Super, Sameer C Dhamne, Alexander Rotenberg, David M Sabatini, Mustafa Sahin, Annapurna Poduri,

DEPDC5 is a newly identified epilepsy-related gene implicated in focal epilepsy, brain malformations, and Sudden Unexplained Death in Epilepsy (SUDEP). In vitro, DEPDC5 negatively regulates amino acid sensing by the mTOR complex 1 (mTORC1) pathway, but the role of DEPDC5 in neurodevelopment and epilepsy has not been described. No animal ... Read more >>

Neurobiol Dis (Neurobiology of disease)
[2018, 111:91-101]

Cited: 32 times

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Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs.

Denise R Minton, Minwoo Nam, Daniel J McLaughlin, Jong Shin, Erol C Bayraktar, Samantha W Alvarez, Vladislav O Sviderskiy, Thales Papagiannakopoulos, David M Sabatini, Kıvanç Birsoy, Richard Possemato,

Upon glucose restriction, eukaryotic cells upregulate oxidative metabolism to maintain homeostasis. Using genetic screens, we find that the mitochondrial serine hydroxymethyltransferase (SHMT2) is required for robust mitochondrial oxygen consumption and low glucose proliferation. SHMT2 catalyzes the first step in mitochondrial one-carbon metabolism, which, particularly in proliferating cells, produces tetrahydrofolate (THF)-conjugated ... Read more >>

Mol Cell (Molecular cell)
[2018, 69(4):610-621.e5]

Cited: 53 times

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mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient.

Gregory A Wyant, Monther Abu-Remaileh, Rachel L Wolfson, Walter W Chen, Elizaveta Freinkman, Laura V Danai, Matthew G Vander Heiden, David M Sabatini,

The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor for the mTORC1 pathway, and we ... Read more >>

Cell (Cell)
[2017, 171(3):642-654.e12]

Cited: 122 times

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SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway.

Xin Gu, Jose M Orozco, Robert A Saxton, Kendall J Condon, Grace Y Liu, Patrycja A Krawczyk, Sonia M Scaria, J Wade Harper, Steven P Gygi, David M Sabatini,

mTOR complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple environmental cues. Nutrients signal via the Rag guanosine triphosphatases (GTPases) to promote the localization of mTORC1 to the lysosomal surface, its site of activation. We identified SAMTOR, a previously uncharacterized protein, which inhibits mTORC1 signaling by interacting ... Read more >>

Science (Science (New York, N.Y.))
[2017, 358(6364):813-818]

Cited: 128 times

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NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis.

Samantha W Alvarez, Vladislav O Sviderskiy, Erdem M Terzi, Thales Papagiannakopoulos, Andre L Moreira, Sylvia Adams, David M Sabatini, Kıvanç Birsoy, Richard Possemato,

Environmental nutrient levels impact cancer cell metabolism, resulting in context-dependent gene essentiality. Here, using loss-of-function screening based on RNA interference, we show that environmental oxygen levels are a major driver of differential essentiality between in vitro model systems and in vivo tumours. Above the 3-8% oxygen concentration typical of most ... Read more >>

Nature (Nature)
[2017, 551(7682):639-643]

Cited: 117 times

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Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes.

Monther Abu-Remaileh, Gregory A Wyant, Choah Kim, Nouf N Laqtom, Maria Abbasi, Sze Ham Chan, Elizaveta Freinkman, David M Sabatini,

The lysosome degrades and recycles macromolecules, signals to the cytosol and nucleus, and is implicated in many diseases. Here, we describe a method for the rapid isolation of mammalian lysosomes and use it to quantitatively profile lysosomal metabolites under various cell states. Under nutrient-replete conditions, many lysosomal amino acids are ... Read more >>

Science (Science (New York, N.Y.))
[2017, 358(6364):807-813]

Cited: 130 times

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Twenty-five years of mTOR: Uncovering the link from nutrients to growth.

David M Sabatini,

In my PNAS Inaugural Article, I describe the development of the mTOR field, starting with efforts to understand the mechanism of action of the drug rapamycin, which ∼25 y ago led to the discovery of the mTOR protein kinase. I focus on insights that we have contributed and on work ... Read more >>

Proc Natl Acad Sci U S A (Proceedings of the National Academy of Sciences of the United States of America)
[2017, 114(45):11818-11825]

Cited: 132 times

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