title: Pathogen signatures activate a ubiquitination pathway that modulates the function of the metabolic checkpoint kinase mTOR.
abstract: The mammalian immune system has the ability to discriminate between pathogenic microbes and nonpathogenic microbes to control inflammation. Here we investigated the ubiquitination profiles of host proteins after infection of macrophages with a virulent strain of the intracellular bacterium Legionella pneumophila or a nonpathogenic mutant of L. pneumophila. Only infection with pathogenic L. pneumophila resulted in ubiquitination of positive regulators of the metabolic checkpoint kinase mTOR and led to diminished mTOR activity. Detection of pathogen signatures resulted in translational biasing toward proinflammatory cytokines through mTOR-mediated regulation of cap-dependent translation. Thus, there is a pathogen-detection program in macrophages that stimulates protein ubiquitination and the degradation of regulators of mTOR, which suppresses mTOR function and directs a proinflammatory cytokine program.
authors.affiliation: Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Stanimir S
authors.initials: SS
authors.lastname: Ivanov
authors.forename: Craig R
authors.initials: CR
authors.lastname: Roy
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000276:immunology; D015151:Immunoblotting; D016952:Legionella pneumophila / Q000235:genetics / Q000276:immunology*; D007877:Legionnaires' Disease / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054875:Ubiquitination / Q000276:immunology*
chemical_list: D016207:Cytokines; D039561:Eukaryotic Initiation Factor-4E; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases