title: Host glycosylation pathways and the unfolded protein response contribute to the infection by Francisella.
abstract: Protein glycosylation processes play a crucial role in most physiological functions, including cell signalling, cellular differentiation and adhesion. We previously demonstrated that rapid deglycosylation of membrane proteins was specifically triggered after infection of human macrophages by the bacterial pathogen Francisella tularensis. Using a glycan processing gene microarray, we found here that Francisella infection modulated expression of numerous glycosidase and glycosyltransferase genes. Furthermore, analysis of cell extracts from infected macrophages by Lectin and Western blotting revealed an important increase of N- and O-protein glycosylation. We chose to focus in the present work on one of the O-glycosylated proteins identified by mass spectrometry, the multifunctional endoplasmic reticulum chaperone BiP (HSPA5/GRP78). We demonstrate that BiP expression is modulated upon Francisella infection and is required to support its intracellular multiplication. Moreover, we show that Francisella differentially modulates the BiP-dependent activation of three key proteins of the unfolded protein response (UPR), IRE1, PERK and ATF6. The effects exerted on human cells by Francisella may thus constitute a novel excample of UPR manipulation contributing to intracellular bacterial adaptation.
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Institut Necker Enfants-Malades INSERM, U1151, Team 11, Unité de Pathogénie des Infections Systémiques, Paris, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Barel
authors.affiliation: Univ. Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, FR 59000, Lille, France.|UGSF, Bat. C9, Université de Lille - Sciences et Technologies, 59655, Villeneuve d'Ascq, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Harduin-Lepers
authors.affiliation: Univ. Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, FR 59000, Lille, France.|UGSF, Bat. C9, Université de Lille - Sciences et Technologies, 59655, Villeneuve d'Ascq, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Portier
authors.affiliation: Univ. Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, FR 59000, Lille, France.|UGSF, Bat. C9, Université de Lille - Sciences et Technologies, 59655, Villeneuve d'Ascq, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Slomianny
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Institut Necker Enfants-Malades INSERM, U1151, Team 11, Unité de Pathogénie des Infections Systémiques, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Charbit
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005604:Francisella tularensis / Q000235:genetics* / Q000254:growth & development; D005786:Gene Expression Regulation; D006026:Glycoside Hydrolases / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D008264:Macrophages / Q000382:microbiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D001426:Bacterial Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D016695:Glycosyltransferases; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases; D006026:Glycoside Hydrolases