The gene encoding the Wiskott-Aldrich syndrome (WAS) protein is transcriptionally repressed following stimulation of peripheral blood mononuclear cells with muramyl dipeptide.

The nucleotide-binding oligomerization domain protein 2, NOD2, is the pattern recognition receptor for muramyl dipeptide, a component of the cell wall of both gram-positive and gram-negative bacteria (1, 2). Sensing of muramyl dipeptide by NOD2 triggers signal transduction downstream of the RIP2 kinase to transcriptionally activate a diverse innate immune gene expression program (3-5). Single nucleotide variants in NOD2 are the strongest genetic risk factors for developing Crohn’s Disease (6, 7), an inflammatory bowel disease (8). By mining a published dataset (9), we found that among the genes whose expression changed most significantly in peripheral blood mononuclear cells (PBMC) stimulated with muramyl dipeptide, genome-wide, was the gene encoding the Wiskott-Aldrich syndrome (WAS) protein (10), a regulator of actin polymerization in hematopoietic cells (11). The WAS gene is mutated in patients with Wiskott-Aldrich syndrome (12), a genetic disorder characterized by thrombocytopenia, eczema, immunodeficiency and lymphoid malignancies (13), and whose symptoms include bloody diarrhea (14, 15). WAS RNA message was transcriptionally repressed following exposure of PBMC to muramyl dipeptide. These data link together a gene, that when mutated in humans leads to gastrointestinal symptoms not dissimilar to those found in patients with Crohn’s Disease, with the ligand for the gene whose product encodes the single most significant genetic variant conferring risk for development of Crohn’s Disease, and further suggest that the actin cytoskeleton may be a central target of gene expression changes effected by NOD2 pattern recognition of MDP.