Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor-{kappa}B activation in muramyl dipeptide recognition.
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)-kappaB in epithelial cells and macrophages, whereas NOD2 mutant 3020insC, which is associated with CD, shows an impaired ability to activate NF-kappaB. 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-kappaB 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-kappaB activation after the recognition of bacterial muramyl dipeptide in intestinal epithelial cells.
Department of Medicine, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Nicolas
N
Barnich
Jose E
JE
Aguirre
Hans-Christian
HC
Reinecker
Ramnik
R
Xavier
Daniel K
DK
Podolsky
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000276:immunology* / Q000378:metabolism; D020816:Amino Acid Motifs / Q000502:physiology; D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism; D019556:COS Cells; D018938:Caco-2 Cells; D002462:Cell Membrane / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology; D007413:Intestinal Mucosa / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D014364:Tryptophan / Q000378:metabolism
D000942:Antigens, Bacterial; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D014364:Tryptophan; D007930:Leucine