The bacterial and cellular determinants controlling the recruitment of mTOR to the Salmonella-containing vacuole

Summary Bacterial invasion results in the rapid induction of an acute state of cytosolic amino acid (AA) starvation, provoked by host membrane damage. Bacteria-induced AA starvation, in turn, down-regulates mTOR signaling while triggering autophagy and the integrated stress response pathway dependent on GCN2, eIF2&agr; and ATF3. In Salmonella-infected cells, we now demonstrate that the host AA starvation response program depended on the Salmonella pathogenicity island (SPI)-1, the activity of which was required to damage the Salmonella-containing vacuole (SCV) in the early stage of infection. At a later stage (3–4 hour post-infection), the progressive recruitment of mTOR to the surface of the SCV appeared to be independent of the activity of SPI-2 and of SCV positioning in the cell. Instead, mTOR localization to the SCV required the activity of host AA transporters SLC1A5, SLC3A2 and SLC7A5, resulting in bacterial escape from autophagy. These results expand our understanding of the mechanisms underlying the AA starvation response in Salmonella-infected cells.

[1]  Andrew Emili,et al.  Amino acid starvation induced by invasive bacterial pathogens triggers an innate host defense program. , 2012, Cell host & microbe.

[2]  F. Randow,et al.  Galectin-8 targets damaged vesicles for autophagy to defend cells against bacterial invasion , 2011, Nature.

[3]  N. Sonenberg,et al.  Leishmania repression of host translation through mTOR cleavage is required for parasite survival and infection. , 2011, Cell host & microbe.

[4]  P. Kim,et al.  The ubiquitin-binding adaptor proteins p62/SQSTM1 and NDP52 are recruited independently to bacteria-associated microdomains to target Salmonella to the autophagy pathway , 2011, Autophagy.

[5]  F. Randow.  How cells deploy ubiquitin and autophagy to defend their cytosol from bacterial invasion , 2011, Autophagy.

[6]  Cahir J. O'Kane,et al.  Lysosomal positioning coordinates cellular nutrient responses , 2011, Nature Cell Biology.

[7]  D. Sabatini,et al.  mTOR: from growth signal integration to cancer, diabetes and ageing , 2010, Nature Reviews Molecular Cell Biology.

[8]  N. Dupont,et al.  How ubiquitination and autophagy participate in the regulation of the cell response to bacterial infection , 2010, Biology of the cell.

[9]  D. Sabatini,et al.  Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. , 2010, Molecular cell.

[10]  D. Klionsky,et al.  A diacylglycerol-dependent signaling pathway contributes to regulation of antibacterial autophagy. , 2010, Cell host & microbe.

[11]  D. Philpott,et al.  NLRC5 Limits the Activation of Inflammatory Pathways , 2010, Journal of Immunology.

[12]  K. Boller,et al.  Pro-autophagic signal induction by bacterial pore-forming toxins , 2010, Medical Microbiology and Immunology.

[13]  V. Deretic.  Autophagy in infection. , 2010, Current opinion in cell biology.

[14]  C. Roy,et al.  NDP52: the missing link between ubiquitinated bacteria and autophagy , 2009, Nature Immunology.

[15]  T. Lamark,et al.  The Adaptor Protein p62/SQSTM1 Targets Invading Bacteria to the Autophagy Pathway1 , 2009, The Journal of Immunology.

[16]  T. Wolff,et al.  Activation of the Antiviral Kinase PKR and Viral Countermeasures , 2009, Viruses.

[17]  D. Sabatini,et al.  mTOR signaling at a glance , 2009, Journal of Cell Science.

[18]  S. Bloor,et al.  The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria , 2009, Nature Immunology.

[19]  M. Colombo,et al.  Autophagy in intracellular bacterial infection. , 2009, Biochimica et biophysica acta.

[20]  V. Deretic,et al.  Autophagy, immunity, and microbial adaptations. , 2009, Cell host & microbe.

[21]  L. Weiss,et al.  Intracellular parasitism with Toxoplasma gondii stimulates mammalian‐target‐of‐rapamycin‐dependent host cell growth despite impaired signalling to S6K1 and 4E‐BP1 , 2009, Cellular microbiology.

[22]  She Chen,et al.  ULK1·ATG13·FIP200 Complex Mediates mTOR Signaling and Is Essential for Autophagy* , 2009, Journal of Biological Chemistry.

[23]  C. Jung,et al.  ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. , 2009, Molecular biology of the cell.

[24]  E. Groisman,et al.  Control of Salmonella pathogenicity island-2 gene expression. , 2009, Current opinion in microbiology.

[25]  J. Guan,et al.  Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. , 2009, Molecular biology of the cell.

[26]  Jeffrey P. MacKeigan,et al.  Bidirectional Transport of Amino Acids Regulates mTOR and Autophagy , 2009, Cell.

[27]  L. Weiss,et al.  Host Cell Autophagy Is Induced by Toxoplasma gondii and Contributes to Parasite Growth* , 2009, Journal of Biological Chemistry.

[28]  Malina A. Bakowski,et al.  Salmonella‐Containing Vacuoles: Directing Traffic and Nesting to Grow , 2008, Traffic.

[29]  Yongjun Yu,et al.  The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K–Akt–mTOR signalling pathway , 2008, Nature Reviews Microbiology.

[30]  O. Steele‐Mortimer.  The Salmonella-containing vacuole: moving with the times. , 2008, Current opinion in microbiology.

[31]  Daniel J. Klionsky,et al.  Autophagy: from phenomenology to molecular understanding in less than a decade , 2007, Nature Reviews Molecular Cell Biology.

[32]  L. J. Mota,et al.  Membrane dynamics and spatial distribution of Salmonella-containing vacuoles. , 2007, Trends in microbiology.

[33]  A. Sharafkhaneh,et al.  Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. , 2007, Immunity.

[34]  P. Lipp,et al.  Localization of protein kinase C ε to macrophage vacuoles perforated by Listeria monocytogenes cytolysin , 2007, Cellular microbiology.

[35]  S. Shorte,et al.  The SPI-2 type III secretion system restricts motility of Salmonella-containing vacuoles , 2007, Cellular microbiology.

[36]  Veronica Canadien,et al.  Listeria monocytogenes Evades Killing by Autophagy During Colonization of Host Cells , 2007, Autophagy.

[37]  M. Lipinski,et al.  Autophagy Limits Listeria monocytogenes Intracellular Growth in the Early Phase of Primary Infection , 2007, Autophagy.

[38]  J. Brumell,et al.  Autophagy Recognizes Intracellular Salmonella enterica serovar Typhimurium in Damaged Vacuoles , 2006, Autophagy.

[39]  C. Sasakawa,et al.  Shigella and Autophagy , 2006, Autophagy.

[40]  Malina A. Bakowski,et al.  Autophagy Controls Salmonella Infection in Response to Damage to the Salmonella-containing Vacuole* , 2006, Journal of Biological Chemistry.

[41]  R. Wek,et al.  Differential Activation of eIF2 Kinases in Response to Cellular Stresses in Schizosaccharomyces pombe , 2004, Genetics.

[42]  I. Jordens,et al.  Dynein-mediated vesicle transport controls intracellular Salmonella replication. , 2004, Molecular biology of the cell.

[43]  E. Caron,et al.  Microtubule motors control membrane dynamics of Salmonella-containing vacuoles , 2004, Journal of Cell Science.

[44]  P. Webster,et al.  Cytoplasmic bacteria can be targets for autophagy , 2003, Cellular microbiology.

[45]  J. Gorvel,et al.  Maturation steps of the Salmonella-containing vacuole. , 2001, Microbes and infection.

[46]  R. Serrano,et al.  The Protein Kinase Gcn2p Mediates Sodium Toxicity in Yeast* , 2001, The Journal of Biological Chemistry.

[47]  D. Jewell,et al.  NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation , 2010, Nature Medicine.

[48]  D. Philpott,et al.  Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry , 2010, Nature Immunology.

[49]  J. Brumell,et al.  Autophagy in immunity against intracellular bacteria. , 2009, Current topics in microbiology and immunology.