title: Salmonella Typhimurium disrupts Sirt1/AMPK checkpoint control of mTOR to impair autophagy.
abstract: During intracellular infections, autophagy significantly contributes to the elimination of pathogens, regulation of pro-inflammatory signaling, secretion of immune mediators and in coordinating the adaptive immune system. Intracellular pathogens such as S. Typhimurium have evolved mechanisms to circumvent autophagy. However, the regulatory mechanisms targeted by S. Typhimurium to modulate autophagy have not been fully resolved. Here we report that cytosolic energy loss during S. Typhimurium infection triggers transient activation of AMPK, an important checkpoint of mTOR activity and autophagy. The activation of AMPK is regulated by LKB1 in a cytosolic complex containing Sirt1 and LKB1, where Sirt1 is required for deacetylation and subsequent activation of LKB1. S. Typhimurium infection targets Sirt1, LKB1 and AMPK to lysosomes for rapid degradation resulting in the disruption of the AMPK-mediated regulation of mTOR and autophagy. The degradation of cytosolic Sirt1/LKB1/AMPK complex was not observed with two mutant strains of S. Typhimurium, ΔssrB and ΔssaV, both compromising the pathogenicity island 2 (SPI2). The results highlight virulence factor-dependent degradation of host cell proteins as a previously unrecognized strategy of S. Typhimurium to evade autophagy.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.|Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Raja
authors.initials: R
authors.lastname: Ganesan
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.|Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.|German Center for Infection Research (DZIF), Cologne, Germany.
authors.forename: Nina Judith
authors.initials: NJ
authors.lastname: Hos
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.|Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Saray
authors.initials: S
authors.lastname: Gutierrez
authors.affiliation: Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.|First Department of Internal Medicine, University of Cologne, Cologne, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Fischer
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.|Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Joanna Magdalena
authors.initials: JM
authors.lastname: Stepek
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.|Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Evmorphia
authors.initials: E
authors.lastname: Daglidu
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.|Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.|German Center for Infection Research (DZIF), Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.|Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Nirmal
authors.identifier: 0000-0002-7361-9491
authors.initials: N
authors.lastname: Robinson
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000502:physiology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D012480:Salmonella Infections / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology / Q000472:pathogenicity; D015398:Signal Transduction / Q000276:immunology; D056564:Sirtuin 1 / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; C419942:Spi1 protein, Salmonella; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1