title: NOD1 and NOD2 signalling links ER stress with inflammation.
abstract: Endoplasmic reticulum (ER) stress is a major contributor to inflammatory diseases, such as Crohn disease and type 2 diabetes. ER stress induces the unfolded protein response, which involves activation of three transmembrane receptors, ATF6, PERK and IRE1α. Once activated, IRE1α recruits TRAF2 to the ER membrane to initiate inflammatory responses via the NF-κB pathway. Inflammation is commonly triggered when pattern recognition receptors (PRRs), such as Toll-like receptors or nucleotide-binding oligomerization domain (NOD)-like receptors, detect tissue damage or microbial infection. However, it is not clear which PRRs have a major role in inducing inflammation during ER stress. Here we show that NOD1 and NOD2, two members of the NOD-like receptor family of PRRs, are important mediators of ER-stress-induced inflammation in mouse and human cells. The ER stress inducers thapsigargin and dithiothreitol trigger production of the pro-inflammatory cytokine IL-6 in a NOD1/2-dependent fashion. Inflammation and IL-6 production triggered by infection with Brucella abortus, which induces ER stress by injecting the type IV secretion system effector protein VceC into host cells, is TRAF2, NOD1/2 and RIP2-dependent and can be reduced by treatment with the ER stress inhibitor tauroursodeoxycholate or an IRE1α kinase inhibitor. The association of NOD1 and NOD2 with pro-inflammatory responses induced by the IRE1α/TRAF2 signalling pathway provides a novel link between innate immunity and ER-stress-induced inflammation.
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: A Marijke
authors.initials: AM
authors.lastname: Keestra-Gounder
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Mariana X
authors.initials: MX
authors.lastname: Byndloss
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Núbia
authors.initials: N
authors.lastname: Seyffert
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Briana M
authors.initials: BM
authors.lastname: Young
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Chávez-Arroyo
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: April Y
authors.initials: AY
authors.lastname: Tsai
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Cevallos
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Winter
authors.affiliation: Center for Comparative Medicine, Schools of Medicine and Veterinary Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Oanh H
authors.initials: OH
authors.lastname: Pham
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Connor R
authors.initials: CR
authors.lastname: Tiffany
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Maarten F
authors.initials: MF
authors.lastname: de Jong
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kerrinnes
authors.affiliation: Center for Comparative Medicine, Schools of Medicine and Veterinary Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Resmi
authors.initials: R
authors.lastname: Ravindran
authors.affiliation: Center for Comparative Medicine, Schools of Medicine and Veterinary Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Luciw
authors.affiliation: Center for Comparative Medicine, Schools of Medicine and Veterinary Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: McSorley
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Bäumler
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.
authors.forename: Renée M
authors.initials: RM
authors.lastname: Tsolis
mesh_terms: D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D002003:Brucella abortus / Q000276:immunology / Q000472:pathogenicity; D002460:Cell Line; D004229:Dithiothreitol / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000276:immunology / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D001425:Bacterial Outer Membrane Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D051192:Receptors, Pattern Recognition; D047992:TNF Receptor-Associated Factor 2; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D019284:Thapsigargin; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D004229:Dithiothreitol