title: Inhibition of host cell translation elongation by Legionella pneumophila blocks the host cell unfolded protein response.
abstract: Cells of the innate immune system recognize bacterial pathogens by detecting common microbial patterns as well as pathogen-specific activities. One system that responds to these stimuli is the IRE1 branch of the unfolded protein response (UPR), a sensor of endoplasmic reticulum (ER) stress. Activation of IRE1, in the context of Toll-like receptor (TLR) signaling, induces strong proinflammatory cytokine induction. We show here that Legionella pneumophila, an intravacuolar pathogen that replicates in an ER-associated compartment, blocks activation of the IRE1 pathway despite presenting pathogen products that stimulate this response. L. pneumophila TLR ligands induced the splicing of mRNA encoding XBP1s, the main target of IRE1 activity. L. pneumophila was able to inhibit both chemical and bacterial induction of XBP1 splicing via bacterial translocated proteins that interfere with host protein translation. A strain lacking five translocated translation elongation inhibitors was unable to block XBP1 splicing, but this could be rescued by expression of a single such inhibitor, consistent with limitation of the response by translation elongation inhibitors. Chemical inhibition of translation elongation blocked pattern recognition receptor-mediated XBP1 splicing, mimicking the effects of the bacterial translation inhibitors. In contrast, host cell-promoted inhibition of translation initiation in response to the pathogen was ineffective in blocking XBP1 splicing, demonstrating the need for the elongation inhibitors for protection from the UPR. The inhibition of host translation elongation may be a common strategy used by pathogens to limit the innate immune response by interfering with signaling via the UPR.
authors.affiliation: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111; Graduate Program in Molecular Microbiology, Tufts University School of Medicine, Boston, MA 02111;
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hempstead
authors.affiliation: Graduate Program in Molecular Microbiology, Tufts University School of Medicine, Boston, MA 02111; Howard Hughes Medical Institute, Tufts University School of Medicine, Boston, MA 02111 ralph.isberg@tufts.edu.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Isberg
mesh_terms: D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics; D004722:Endoribonucleases / Q000502:physiology; D006801:Humans; D016952:Legionella pneumophila / Q000502:physiology*; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D003513:Cycloheximide; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
keywords: Legionella; translation inhibition; unfolded protein response