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2. Positive and Negative Regulation of the Master Metabolic Regulator mTORC1 by Two Families of Legionella pneumophila Effectors

Author

De Leon, Justin A, Qiu, Jiazhang, Nicolai, Christopher J, Counihan, Jessica L, Barry, Kevin C, Xu, Li, Lawrence, Rosalie E, Castellano, Brian M, Zoncu, Roberto, Nomura, Daniel K, Luo, Zhao-Qing, and Vance, Russell E

Subjects
Biochemistry and Cell Biology, Biological Sciences, Pneumonia, Infectious Diseases, Pneumonia & Influenza, Lung, Rare Diseases, 2.1 Biological and endogenous factors, Bacterial Proteins, Carrier Proteins, Host-Pathogen Interactions, Legionella pneumophila, Legionnaires' Disease, Mechanistic Target of Rapamycin Complex 1, Membrane Proteins, Protein Transport, T4SS, amino acids, amino-acids, effector, mTORC1, Medical Physiology, Biological sciences
Abstract

All pathogens must acquire nutrients from their hosts. The intracellular bacterial pathogen Legionella pneumophila, the etiological agent of Legionnaires' disease, requires host amino acids for growth within cells. The mechanistic target of rapamycin complex 1 (mTORC1) is an evolutionarily conserved master regulator of host amino acid metabolism. Here, we identify two families of translocated L. pneumophila effector proteins that exhibit opposing effects on mTORC1 activity. The Legionella glucosyltransferase (Lgt) effector family activates mTORC1, through inhibition of host translation, whereas the SidE/SdeABC (SidE) effector family acts as mTORC1 inhibitors. We demonstrate that a common activity of both effector families is to inhibit host translation. We propose that the Lgt and SidE families of effectors work in concert to liberate host amino acids for consumption by L. pneumophila.

Published
2017

4. Lysosomal cholesterol activates mTORC1 via an SLC38A9–Niemann-Pick C1 signaling complex

Author

Castellano, Brian M, Thelen, Ashley M, Moldavski, Ofer, Feltes, McKenna, van der Welle, Reini EN, Mydock-McGrane, Laurel, Jiang, Xuntian, van Eijkeren, Robert J, Davis, Oliver B, Louie, Sharon M, Perera, Rushika M, Covey, Douglas F, Nomura, Daniel K, Ory, Daniel S, and Zoncu, Roberto

Subjects
Underpinning research, 1.1 Normal biological development and functioning, Amino Acid Motifs, Amino Acid Transport Systems, Animals, Biological Transport, CHO Cells, Carrier Proteins, Cholesterol, Cholesterol, HDL, Cricetulus, Enzyme Activation, Fibroblasts, HEK293 Cells, Humans, Lysosomes, Mechanistic Target of Rapamycin Complex 1, Mice, Multiprotein Complexes, Mutation, Nuclear Proteins, Signal Transduction, TOR Serine-Threonine Kinases, General Science & Technology
Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that becomes activated at the lysosome in response to nutrient cues. Here, we identify cholesterol, an essential building block for cellular growth, as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface. The lysosomal transmembrane protein, SLC38A9, is required for mTORC1 activation by cholesterol through conserved cholesterol-responsive motifs. Moreover, SLC38A9 enables mTORC1 activation by cholesterol independently from its arginine-sensing function. Conversely, the Niemann-Pick C1 (NPC1) protein, which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function. Thus, lysosomal cholesterol drives mTORC1 activation and growth signaling through the SLC38A9-NPC1 complex.

Published
2017

5. Activation of the PERK branch of the unfolded protein response during production reduces specific productivity in CHO cells via downregulation of PDGFRa and IRE1a signaling

Author

Castellano, Brian M., primary, Tang, Danming, additional, Marsters, Scot, additional, Lam, Cynthia, additional, Liu, Peter, additional, Rose, Christopher M., additional, Sandoval, Wendy, additional, Ashkenazi, Avi, additional, Snedecor, Brad, additional, and Misaghi, Shahram, additional

Published
2023
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7. Erratum: Corrigendum: Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

Author

Okosun, Jessica, primary, Wolfson, Rachel L, additional, Wang, Jun, additional, Araf, Shamzah, additional, Wilkins, Lucy, additional, Castellano, Brian M, additional, Escudero-Ibarz, Leire, additional, Seraihi, Ahad Fahad Al, additional, Richter, Julia, additional, Bernhart, Stephan H, additional, Efeyan, Alejo, additional, Iqbal, Sameena, additional, Matthews, Janet, additional, Clear, Andrew, additional, Guerra-Assunção, José Afonso, additional, Bödör, Csaba, additional, Quentmeier, Hilmar, additional, Mansbridge, Christopher, additional, Johnson, Peter, additional, Davies, Andrew, additional, Strefford, Jonathan C, additional, Packham, Graham, additional, Barrans, Sharon, additional, Jack, Andrew, additional, Du, Ming-Qing, additional, Calaminici, Maria, additional, Lister, T Andrew, additional, Auer, Rebecca, additional, Montoto, Silvia, additional, Gribben, John G, additional, Siebert, Reiner, additional, Chelala, Claude, additional, Zoncu, Roberto, additional, Sabatini, David M, additional, and Fitzgibbon, Jude, additional

Published
2016
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8. Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

Author

Okosun, Jessica, primary, Wolfson, Rachel L, additional, Wang, Jun, additional, Araf, Shamzah, additional, Wilkins, Lucy, additional, Castellano, Brian M, additional, Escudero-Ibarz, Leire, additional, Al Seraihi, Ahad Fahad, additional, Richter, Julia, additional, Bernhart, Stephan H, additional, Efeyan, Alejo, additional, Iqbal, Sameena, additional, Matthews, Janet, additional, Clear, Andrew, additional, Guerra-Assunção, José Afonso, additional, Bödör, Csaba, additional, Quentmeier, Hilmar, additional, Mansbridge, Christopher, additional, Johnson, Peter, additional, Davies, Andrew, additional, Strefford, Jonathan C, additional, Packham, Graham, additional, Barrans, Sharon, additional, Jack, Andrew, additional, Du, Ming-Qing, additional, Calaminici, Maria, additional, Lister, T Andrew, additional, Auer, Rebecca, additional, Montoto, Silvia, additional, Gribben, John G, additional, Siebert, Reiner, additional, Chelala, Claude, additional, Zoncu, Roberto, additional, Sabatini, David M, additional, and Fitzgibbon, Jude, additional

Published
2015
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11. Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

Author

Okosun, Jessica, Wolfson, Rachel L, Wang, Jun, Araf, Shamzah, Wilkins, Lucy, Castellano, Brian M, Escudero-Ibarz, Leire, Al Seraihi, Ahad Fahad, Richter, Julia, Bernhart, Stephan H, Efeyan, Alejo, Iqbal, Sameena, Matthews, Janet, Clear, Andrew, Guerra-Assunção, José Afonso, Bödör, Csaba, Quentmeier, Hilmar, Mansbridge, Christopher, Johnson, Peter, Davies, Andrew, Strefford, Jonathan C, Packham, Graham, Barrans, Sharon, Jack, Andrew, Du, Ming-Qing, Calaminici, Maria, Lister, T Andrew, Auer, Rebecca, Montoto, Silvia, Gribben, John G, Siebert, Reiner, Chelala, Claude, Zoncu, Roberto, Sabatini, David M, and Fitzgibbon, Jude

Abstract

Follicular lymphoma is an incurable B cell malignancy characterized by the t(14;18) translocation and mutations affecting the epigenome. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlaps with that in the closely related diffuse large B cell lymphoma (DLBCL). Using a combination of discovery exome and extended targeted sequencing, we identified recurrent somatic mutations in RRAGC uniquely enriched in patients with follicular lymphoma (17%). More than half of the mutations preferentially co-occurred with mutations in ATP6V1B2 and ATP6AP1, which encode components of the vacuolar H+-ATP ATPase (V-ATPase) known to be necessary for amino acid−induced activation of mTORC1. The RagC variants increased raptor binding while rendering mTORC1 signaling resistant to amino acid deprivation. The activating nature of the RRAGC mutations, their existence in the dominant clone and their stability during disease progression support their potential as an excellent candidate for therapeutic targeting.

Published
2016
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12. Corrigendum: Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

Author

Okosun, Jessica, Wolfson, Rachel L, Wang, Jun, Araf, Shamzah, Wilkins, Lucy, Castellano, Brian M, Escudero-Ibarz, Leire, Seraihi, Ahad Fahad Al, Richter, Julia, Bernhart, Stephan H, Efeyan, Alejo, Iqbal, Sameena, Matthews, Janet, Clear, Andrew, Guerra-Assunção, José Afonso, Bödör, Csaba, Quentmeier, Hilmar, Mansbridge, Christopher, Johnson, Peter, Davies, Andrew, Strefford, Jonathan C, Packham, Graham, Barrans, Sharon, Jack, Andrew, Du, Ming-Qing, Calaminici, Maria, Lister, T Andrew, Auer, Rebecca, Montoto, Silvia, Gribben, John G, Siebert, Reiner, Chelala, Claude, Zoncu, Roberto, Sabatini, David M, and Fitzgibbon, Jude

Published
2016
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