The Immune Receptor NOD1 and Kinase RIP2 Interact with Bacterial Peptidoglycan on Early Endosomes to Promote Autophagy and Inflammatory Signaling

• Published in: Cell host & microbe Vol. 15; no. 5; pp. 623 - 635
• Main Authors: Irving, Aaron T., Mimuro, Hitomi, Kufer, Thomas A., Lo, Camden, Wheeler, Richard, Turner, Lorinda J., Thomas, Belinda J., Malosse, Christian, Gantier, Michael P., Casillas, Linda N., Votta, Bartholomew J., Bertin, John, Boneca, Ivo G., Sasakawa, Chihiro, Philpott, Dana J., Ferrero, Richard L., Kaparakis-Liaskos, Maria
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.05.2014
• Subjects: Animals; Autophagy; Cell Line; Endosomes - immunology; Endosomes - microbiology; Helicobacter Infections - enzymology; Helicobacter Infections - genetics; Helicobacter Infections - immunology; Helicobacter pylori - immunology; Helicobacter pylori - physiology; Humans; Mice; Nod1 Signaling Adaptor Protein - genetics; Nod1 Signaling Adaptor Protein - immunology; Peptidoglycan - immunology; Protein Binding; Pseudomonas aeruginosa - immunology; Pseudomonas aeruginosa - physiology; Pseudomonas Infections - enzymology; Pseudomonas Infections - genetics; Pseudomonas Infections - immunology; Receptor-Interacting Protein Serine-Threonine Kinase 2 - genetics; Receptor-Interacting Protein Serine-Threonine Kinase 2 - immunology; Receptors, Immunologic - genetics; Receptors, Immunologic - immunology; Signal Transduction
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2014.04.001

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. [Display omitted] •Bacterial outer membrane vesicles (OMVs) induce autophagy in epithelial cells•NOD1 and RIP2 are essential for autophagy and inflammatory IL-8 responses to OMVs•NOD1 and RIP2 associate with OMV peptidoglycan (PG) in EEA1-positive early endosomes•NOD1 interacts directly with PG-OMVs and RIP2 at early endosomes The intracellular innate immune receptor NOD1 detects Gram-negative bacterial peptidoglycan; however, details regarding the mechanisms whereby this process occurs remain unknown. Irving et al. identify that NOD1 interacts with bacterial delivered peptidoglycan and RIP2 in early endosomes, facilitating the development of autophagy and IL-8 production in a RIP2-dependent manner.