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Sci. Signal., 15 January 2013
Vol. 6, Issue 258, p. rs3
[DOI: 10.1126/scisignal.2003305]


A Genome-Wide siRNA Screen Reveals Positive and Negative Regulators of the NOD2 and NF-{kappa}B Signaling Pathways

Neil Warner1*, Aaron Burberry1*, Luigi Franchi1, Yun-Gi Kim1, Christine McDonald2, Maureen A. Sartor3,4, and Gabriel Núñez1,3{dagger}

1 Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
2 Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH 44195, USA.
3 Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
4 Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.

* These authors contributed equally to this work.

Abstract: The cytoplasmic receptor NOD2 (nucleotide-binding oligomerization domain 2) senses peptidoglycan fragments and triggers host defense pathways, including activation of nuclear factor {kappa}B (NF-{kappa}B) 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-{kappa}B signaling, thus supporting a role for NOD2 and NF-{kappa}B 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-{kappa}B. 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-{kappa}B signaling. Overall, the genes identified here provide a resource to facilitate the elucidation of the molecular mechanisms that regulate NOD2- and NF-{kappa}B–mediated inflammation.

{dagger} To whom correspondence should be addressed. E-mail: bclx{at}

Citation: N. Warner, A. Burberry, L. Franchi, Y.-G. Kim, C. McDonald, M. A. Sartor, G. Núñez, A Genome-Wide siRNA Screen Reveals Positive and Negative Regulators of the NOD2 and NF-{kappa}B Signaling Pathways. Sci. Signal. 6, rs3 (2013).

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