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

• Published in: Cell reports (Cambridge) 2017-11, Vol.21 (8), p.2031-2038
• Main Authors: 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, Vance, Russell E.
• Format: Article
• Language: English
• Subjects: amino acids; Bacterial Proteins - metabolism; Carrier Proteins - metabolism; effector; Host-Pathogen Interactions - physiology; Legionella pneumophila; Legionella pneumophila - metabolism; Legionnaires' Disease - metabolism; Mechanistic Target of Rapamycin Complex 1 - metabolism; Membrane Proteins - metabolism; mTORC1; Protein Transport - physiology; T4SS
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.10.088

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. [Display omitted] •The human pathogen L. pneumophila secretes effectors that modulate mTORC1•The Lgt effector family activates mTORC1 upstream of the Rag small GTPases•The SidE family inhibits mTORC1 via direct ubiquitylation of Rag small GTPases•Lgt and SidE families work in concert to free amino acids for bacterial consumption Pathogens manipulate host metabolism in order to acquire nutrients during infection. De Leon, Qiu, et al. show how the bacterial pathogen Legionella pneumophila targets mTORC1, a key nutrient signaling hub in host cells, by secreting two families of effectors that act via distinct mechanisms.