title: ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria.
abstract: During infection by invasive bacteria, epithelial cells contribute to innate immunity via the local secretion of inflammatory cytokines. These are directly produced by infected cells or by uninfected bystanders via connexin-dependent cell-cell communication. However, the cellular pathways underlying this process remain largely unknown. Here we perform a genome-wide RNA interference screen and identify TIFA and TRAF6 as central players of Shigella flexneri and Salmonella typhimurium-induced interleukin-8 expression. We show that threonine 9 and the forkhead-associated domain of TIFA are necessary for the oligomerization of TIFA in both infected and bystander cells. Subsequently, this process triggers TRAF6 oligomerization and NF-κB activation. We demonstrate that TIFA/TRAF6-dependent cytokine expression is induced by the bacterial metabolite heptose-1,7-bisphosphate (HBP). In addition, we identify alpha-kinase 1 (ALPK1) as the critical kinase responsible for TIFA oligomerization and IL-8 expression in response to infection with S. flexneri and S. typhimurium but also to Neisseria meningitidis. Altogether, these results clearly show that ALPK1 is a master regulator of innate immunity against both invasive and extracellular gram-negative bacteria.
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France, CNRS, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Milica
authors.initials: M
authors.lastname: Milivojevic
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France, CNRS, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Anne-Sophie
authors.identifier: 0000-0002-8974-9012
authors.initials: AS
authors.lastname: Dangeard
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Christoph Alexander
authors.initials: CA
authors.lastname: Kasper
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Therese
authors.initials: T
authors.lastname: Tschon
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Emmenlauer
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France, CNRS, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Pique
authors.affiliation: Institut Imagine, UMR_S1163, Paris, France.
authors.forename: Pamela
authors.identifier: 0000-0003-4292-1257
authors.initials: P
authors.lastname: Schnupf
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France, CNRS, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Julie
authors.identifier: 0000-0001-8890-4028
authors.initials: J
authors.lastname: Guignot
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France, CNRS, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Cécile
authors.identifier: 0000-0002-6463-2897
authors.initials: C
authors.lastname: Arrieumerlou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D018925:Chemokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000276:immunology; D005455:Fluorescent Antibody Technique; D006090:Gram-Negative Bacteria / Q000276:immunology; D016905:Gram-Negative Bacterial Infections / Q000276:immunology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006539:Heptoses / Q000276:immunology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007113:Immunity, Innate / Q000276:immunology*; D015151:Immunoblotting; D047468:Immunoprecipitation; D009345:Neisseria meningitidis / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology; D012763:Shigella flexneri / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; D006539:Heptoses; C446759:TIFA protein, human; D048029:TNF Receptor-Associated Factor 6