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Published 5 July 2005. doi:10.1083/jcb.200502153
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 1, 21-26
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 Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor–{kappa}B activation in muramyl dipeptide recognition

Nicolas Barnich, Jose E. Aguirre, Hans-Christian Reinecker, Ramnik Xavier, and Daniel K. Podolsky

Gastrointestinal Unit, Department of Medicine, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114

Correspondence to Daniel K. Podolsky: dpodolsky{at}partners.org


Abstract
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)–{kappa}B in epithelial cells and macrophages, whereas NOD2 mutant 3020insC, which is associated with CD, shows an impaired ability to activate NF-{kappa}B. 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-{kappa}B 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-{kappa}B activation after the recognition of bacterial muramyl dipeptide in intestinal epithelial cells.

Abbreviations used in this paper: CARD, caspase activation and recruitment domain; CD, Crohn's disease; MDP, muramyl dipeptide; NOD2, nucleotide oligomerization domain 2; NF, nuclear factor; RICK, RIP-like interacting caspase-like apoptosis regulatory protein kinase.


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