title: The immune receptor NOD1 and kinase RIP2 interact with bacterial peptidoglycan on early endosomes to promote autophagy and inflammatory signaling.
abstract: The intracellular innate immune receptor NOD1 detects Gram-negative bacterial peptidoglycan (PG) to induce autophagy and inflammatory responses in host cells. To date, the intracellular compartment in which PG is detected by NOD1 and whether NOD1 directly interacts with PG are two questions that remain to be resolved. To address this, we used outer membrane vesicles (OMVs) from pathogenic bacteria as a physiological mechanism to deliver PG into the host cell cytosol. We report that OMVs induced autophagosome formation and inflammatory IL-8 responses in epithelial cells in a NOD1- and RIP2-dependent manner. PG contained within OMVs colocalized with both NOD1 and RIP2 in EEA1-positive early endosomes. Further, we provide evidence for direct interactions between NOD1 and PG. Collectively, these findings demonstrate that NOD1 detects PG within early endosomes, thereby promoting RIP2-dependent autophagy and inflammatory signaling in response to bacterial infection.
authors.affiliation: Centre for Cancer Research, Monash Institute of Medical Research, Clayton, VIC 3168, Australia.
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Irving
authors.affiliation: Division of Bacteriology, Department of Infectious Diseases Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Mimuro
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Köln 50931, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kufer
authors.affiliation: Monash Micro Imaging, Clayton, VIC 3168, Australia.
authors.forename: Camden
authors.initials: C
authors.lastname: Lo
authors.affiliation: Institut Pasteur, Unité Biologie et Génétique de la Paroi Bactérienne, Paris 75015, France; INSERM, Avenir group, Paris 75015, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Wheeler
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Clayton, VIC 3168, Australia.
authors.forename: Lorinda J
authors.initials: LJ
authors.lastname: Turner
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Clayton, VIC 3168, Australia; Monash Lung and Sleep, Monash Medical Centre, Clayton, VIC 3168, Australia.
authors.forename: Belinda J
authors.initials: BJ
authors.lastname: Thomas
authors.affiliation: Institut Pasteur, Structural Mass Spectrometry and Proteomics Unit, Paris 75015, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Malosse
authors.affiliation: Centre for Cancer Research, Monash Institute of Medical Research, Clayton, VIC 3168, Australia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Gantier
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapy Area, GlaxoSmithKline, Collegeville, PA 19426-0989, USA.
authors.forename: Linda N
authors.initials: LN
authors.lastname: Casillas
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapy Area, GlaxoSmithKline, Collegeville, PA 19426-0989, USA.
authors.forename: Bartholomew J
authors.initials: BJ
authors.lastname: Votta
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapy Area, GlaxoSmithKline, Collegeville, PA 19426-0989, USA.
authors.forename: John
authors.initials: J
authors.lastname: Bertin
authors.affiliation: Institut Pasteur, Unité Biologie et Génétique de la Paroi Bactérienne, Paris 75015, France; INSERM, Avenir group, Paris 75015, France.
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Boneca
authors.affiliation: Division of Bacterial Infection Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Nippon Institute for Biological Science, Tokyo 198-0024, Japan; Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sasakawa
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Clayton, VIC 3168, Australia.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Ferrero
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Clayton, VIC 3168, Australia. Electronic address: maria.liaskos@monash.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Kaparakis-Liaskos
mesh_terms: D000818:Animals; D001343:Autophagy; D002460:Cell Line; D011992:Endosomes / Q000276:immunology* / Q000382:microbiology; D016481:Helicobacter Infections / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology* / Q000502:physiology; D006801:Humans; D051379:Mice; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology*; D010457:Peptidoglycan / Q000276:immunology*; D011485:Protein Binding; D011552:Pseudomonas Infections / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D011550:Pseudomonas aeruginosa / Q000276:immunology* / Q000502:physiology; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D053474:Nod1 Signaling Adaptor Protein; D010457:Peptidoglycan; D011971:Receptors, Immunologic; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2