title: Intracellular Bacterial Pathogens Trigger the Formation of U Small Nuclear RNA Bodies (U Bodies) through Metabolic Stress Induction.
abstract: Invasive bacterial pathogens induce an amino acid starvation (AAS) response in infected host cells that controls host defense in part by promoting autophagy. However, whether AAS has additional significant effects on the host response to intracellular bacteria remains poorly characterized. Here we showed that Shigella, Salmonella, and Listeria interfere with spliceosomal U snRNA maturation in the cytosol. Bacterial infection resulted in the rerouting of U snRNAs and their cytoplasmic escort, the survival motor neuron (SMN) complex, to processing bodies, thus forming U snRNA bodies (U bodies). This process likely contributes to the decline in the cytosolic levels of U snRNAs and of the SMN complex proteins SMN and DDX20 that we observed in infected cells. U body formation was triggered by membrane damage in infected cells and was associated with the induction of metabolic stresses, such as AAS or endoplasmic reticulum stress. Mechanistically, targeting of U snRNAs to U bodies was regulated by translation initiation inhibition and the ATF4/ATF3 pathway, and U bodies rapidly disappeared upon removal of the stress, suggesting that their accumulation represented an adaptive response to metabolic stress. Importantly, this process likely contributed to shape the host response to invasive bacteria because down-regulation of DDX20 expression using short hairpin RNA (shRNA) amplified ATF3- and NF-κB-dependent signaling. Together, these results identify a critical role for metabolic stress and invasive bacterial pathogens in U body formation and suggest that this process contributes to host defense.
authors.affiliation: Departments of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M6G 2T6, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tsalikis
authors.affiliation: Departments of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M6G 2T6, Canada; Departments of Immunology, University of Toronto, Toronto M6G 2T6, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Tattoli
authors.affiliation: Departments of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M6G 2T6, Canada.
authors.forename: Arthur
authors.initials: A
authors.lastname: Ling
authors.affiliation: Departments of Immunology, University of Toronto, Toronto M6G 2T6, Canada.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Sorbara
authors.affiliation: Departments of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M6G 2T6, Canada.
authors.forename: David O
authors.initials: DO
authors.lastname: Croitoru
authors.affiliation: Departments of Immunology, University of Toronto, Toronto M6G 2T6, Canada.
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.affiliation: Departments of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M6G 2T6, Canada. Electronic address: stephen.girardin@utoronto.ca.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism / Q000382:microbiology; D055541:DEAD Box Protein 20 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D008089:Listeria monocytogenes / Q000378:metabolism* / Q000472:pathogenicity; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010442:Peptide Chain Initiation, Translational; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012342:RNA, Small Nuclear / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D012486:Salmonella typhimurium / Q000378:metabolism* / Q000472:pathogenicity; D012763:Shigella flexneri / Q000378:metabolism* / Q000472:pathogenicity; D015398:Signal Transduction; D017381:Spliceosomes / Q000378:metabolism / Q000382:microbiology; D013312:Stress, Physiological / Q000235:genetics*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C490449:ATF3 protein, human; C497109:ATF4 protein, human; D051700:Activating Transcription Factor 3; D016328:NF-kappa B; D034741:RNA, Small Interfering; D012342:RNA, Small Nuclear; D055533:Survival of Motor Neuron 1 Protein; D051701:Activating Transcription Factor 4; C120168:DDX20 protein, human; D055541:DEAD Box Protein 20
keywords: Listeria; NF-κB; Salmonella enterica; Shigella; U snRNA; amino acid; endoplasmic reticulum stress (ER stress); infection; metabolic stress