Details

Autor(en) / Beteiligte

• Lecat, Aurore
• Di Valentin, Emmanuel
• Somja, Joan
• Jourdan, Samuel
• Fillet, Marianne
• Kufer, Thomas A.
• Habraken, Yvette
• Sadzot, Catherine
• Louis, Edouard
• Delvenne, Philippe
• Piette, Jacques
• Legrand-Poels, Sylvie

Titel

The c-Jun N-terminal Kinase (JNK)-binding Protein (JNKBP1) Acts as a Negative Regulator of NOD2 Protein Signaling by Inhibiting Its Oligomerization Process

Ist Teil von

• The Journal of biological chemistry, 2012-08, Vol.287 (35), p.29213-29226

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• NOD2 is one of the best characterized members of the cytosolic NOD-like receptor family. NOD2 is able to sense muramyl dipeptide, a specific bacterial cell wall component, and to subsequently induce various signaling pathways leading to NF-κB activation and autophagy, both events contributing to an efficient innate and adaptive immune response. Interestingly, loss-of-function NOD2 variants were associated with a higher susceptibility for Crohn disease, which highlights the physiological importance of proper regulation of NOD2 activity. We performed a biochemical screen to search for new NOD2 regulators. We identified a new NOD2 partner, c-Jun N-terminal kinase-binding protein 1 (JNKBP1), a scaffold protein characterized by an N-terminal WD-40 domain. JNKBP1, through its WD-40 domain, binds to NOD2 following muramyl dipeptide activation. This interaction attenuates NOD2-mediated NF-κB activation and IL-8 secretion as well as NOD2 antibacterial activity. JNKBP1 exerts its repressor effect by disturbing NOD2 oligomerization and RIP2 tyrosine phosphorylation, both steps required for downstream NOD2 signaling. We furthermore showed that JNKBP1 and NOD2 are co-expressed in the human intestinal epithelium and in immune cells recruited in the lamina propria, which suggests that JNKBP1 contributes to maintain NOD2-mediated intestinal immune homeostasis. Background: NOD2 belongs to the NLR family. JNKBP1, a scaffold protein, is characterized by an N-terminal WD-40 domain. Results: JNKBP1 is co-expressed with NOD2 in epithelial and immune cells of intestine mucosa. Binding of JNKB1 to NOD2 attenuates NOD2 signaling by inhibiting its oligomerization. Conclusion: JNKBP1 is a new NOD2 modulator. Significance: JNKBP1, by down-regulating NOD2 signaling, could contribute to maintaining intestinal immune homeostasis.