Membrane Recruitment of NOD2 in Intestinal Epithelial Cells Is Essential for Nuclear Factor-κB Activation in Muramyl Dipeptide Recognition

• Published in: The Journal of cell biology 2005-07, Vol.170 (1), p.21-26
• Main Authors: Barnich, Nicolas, Aguirre, Jose E., Reinecker, Hans-Christian, Xavier, Ramnik, Podolsky, Daniel K.
• Format: Article
• Language: English
• Subjects: Amino acids; Antibodies; Antiserum; Caco 2 cells; Cell membranes; Crohn disease; Epithelial cells; HEK293 cells; P branes; String theory
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200502153

Nucleotide oligomerization domain (NOD) 2 functions as a mammalian cytosolic pathogen recognition molecule, and mutant forms have been genetically linked to Crohn's disease (CD). NOD2 associates with the caspase activation and recruitment domain of RIP-like interacting caspase-like apoptosis regulatory protein kinase (RICK)/RIP2 and activates nuclear factor (NF)-κB in epithelial cells and macrophages, whereas NOD2 mutant 3020insC, which is associated with CD, shows an impaired ability to activate NF-κB. To gain insight into the molecular mechanisms of NOD2 function, we performed a functional analysis of deletion and substitution NOD2 mutants. NOD2, but not NOD2 3020insC mutant, associated with cell surface membranes of intestinal epithelial cells. Membrane targeting and subsequent NF-κB activation are mediated by two leucine residues and a tryptophan-containing motif in the COOH-terminal domain of NOD2. The membrane targeting of NOD2 is required for NF-κB activation after the recognition of bacterial muramyl dipeptide in intestinal epithelial cells.