Journal
CURRENT BIOLOGY
Volume 14, Issue 24, Pages 2217-2227Publisher
CELL PRESS
DOI: 10.1016/j.cub.2004.12.032
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Funding
- NIAID NIH HHS [1K08 AI53819-01A1] Funding Source: Medline
- NIDDK NIH HHS [DK43351] Funding Source: Medline
- NIGMS NIH HHS [GM56203, R01 GM056203] Funding Source: Medline
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Background: Crohn's disease is an autoimmune inflammatory disorder of the gastrointestinal tract and is characterized clinically by dysregulation of both pro-inflammatory and anti-inflammatory cytokine signaling networks. The function of the Crohn's disease protein, NOD2, highlights the biphasic nature of the pathology of Crohn's disease. NOD2 can both strongly activate and negatively attenuate NF-kB signaling. The biochemical mechanism for this dual function of NOD2 is unknown. Results: We demonstrate that NOD2 activation leads to ubiquitinylation of NEMO, a key component of the NF- kB signaling complex. This ubiquitinylation is agonist dependant, and it does not regulate proteosomal destruction of NEMO. We show the NOD2-dependent ubiquitinylation of NEMO is dependent on the scaffolding protein kinase RIP2. Crohn's disease-associated polymorphisms of NOD2 show a decreased ability to bind RIP2, and this decreased ability to bind RIP2 correlates with a decreased ability to ubiquitinylate NEMO. We map the site of NEMO ubiquitinylation to a novel NEMO ubiquitinylation site (Lysine 285) and show that this ubiquityinylation occurs in vivo. Lastly, we show functionally that RIP2-induced ubiquitinylation of NEMO is at least in part responsible for RIP2-mediated NF-kB activation. Conclusions: These data suggest that this novel mode of regulation of the NF-kB signaling pathway could be a factor underlying the pathogenesis of Crohn's disease.
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