title: A genome-wide siRNA screen reveals positive and negative regulators of the NOD2 and NF-κB signaling pathways.
abstract: The cytoplasmic receptor NOD2 (nucleotide-binding oligomerization domain 2) senses peptidoglycan fragments and triggers host defense pathways, including activation of nuclear factor κB (NF-κB) signaling, which lead to inflammatory immune responses. Dysregulation of NOD2 signaling is associated with inflammatory diseases, such as Crohn's disease and Blau syndrome. We used a genome-wide small interfering RNA screen to identify regulators of the NOD2 signaling pathway. Several genes associated with Crohn's disease risk were identified in the screen. A comparison of candidates from this screen with other "omics" data sets revealed interconnected networks of genes implicated in NF-κB signaling, thus supporting a role for NOD2 and NF-κB pathways in the pathogenesis of Crohn's disease. Many of these regulators were validated in secondary assays, such as measurement of interleukin-8 secretion, which is partially dependent on NF-κB. Knockdown of putative regulators in human embryonic kidney 293 cells followed by stimulation with tumor necrosis factor-α revealed that most of the genes identified were general regulators of NF-κB signaling. Overall, the genes identified here provide a resource to facilitate the elucidation of the molecular mechanisms that regulate NOD2- and NF-κB-mediated inflammation.
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Neil
authors: N
authors: Warner
authors: Aaron
authors: A
authors: Burberry
authors: Luigi
authors: L
authors: Franchi
authors: Yun-Gi
authors: YG
authors: Kim
authors: Christine
authors: C
authors: McDonald
authors: Maureen A
authors: MA
authors: Sartor
authors: Gabriel
authors: G
authors: Núñez
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D003424:Crohn Disease / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D015894:Genome, Human / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008957:Models, Genetic; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D020928:Mitogen-Activated Protein Kinases