A genome-wide siRNA screen reveals positive and negative regulators of the NOD2 and NF-κB signaling pathways

Neil Warner, Aaron Burberry, Luigi Franchi, Yungi Kim, Christine McDonald, Maureen A. Sartor, Gabriel Núñez

Research output: Contribution to journalArticle

44 Citations (Scopus)

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 (siRNA) 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 (HEK 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-κBmediated inflammation.

Original languageEnglish
JournalScience Signaling
Volume6
Issue number258
DOIs
Publication statusPublished - 2013 Jan 15
Externally publishedYes

Fingerprint

Oligomerization
Small Interfering RNA
Nucleotides
Genes
Genome
Crohn Disease
Peptidoglycan
Gene Regulatory Networks
Cytoplasmic and Nuclear Receptors
Interleukin-8
Assays
Tumor Necrosis Factor-alpha
Chemical activation
Inflammation
Kidney

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

A genome-wide siRNA screen reveals positive and negative regulators of the NOD2 and NF-κB signaling pathways. / Warner, Neil; Burberry, Aaron; Franchi, Luigi; Kim, Yungi; McDonald, Christine; Sartor, Maureen A.; Núñez, Gabriel.

In: Science Signaling, Vol. 6, No. 258, 15.01.2013.

Research output: Contribution to journalArticle

Warner, Neil ; Burberry, Aaron ; Franchi, Luigi ; Kim, Yungi ; McDonald, Christine ; Sartor, Maureen A. ; Núñez, Gabriel. / A genome-wide siRNA screen reveals positive and negative regulators of the NOD2 and NF-κB signaling pathways. In: Science Signaling. 2013 ; Vol. 6, No. 258.
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