Splicing of NOD2 (CARD15) RNA transcripts

Mutated variants of NOD2, a cytosolic Toll-like receptor (TLR) that recognizes bacterial peptidoglycan, are responsible for increased susceptibility to Crohn's disease (CD). TLRs and their related plant counterparts, the disease-resistance R proteins, undergo alternative splicing as a means of controlling activity. Here we report that regions of NOD2 RNA transcripts that encode the N-terminal and leucine-rich repeat (LRR) domains are alternatively spliced, potentially creating at least eight putative NOD2 variants. The most common variant is a short truncated isoform designated NOD2-short which terminates at residue position 820 leaving three LRR domains. An N-terminally spliced variant designated NOD2-190 contains only CARD1 and a partial CARD2 domain. The expression of transcripts encoding full-length and alternatively spliced forms of NOD2 was altered in blood mononuclear cells and monocytic cell lines stimulated by bacterial products. NOD2-short and NOD2-190 were inactive and unresponsive to muramyl dipeptide (MDP), but did not antagonize the activity of wild-type NOD2. Alternative splicing of NOD2 transcripts represents a potential mechanism by which the intracellular bacterial sensing activity of NOD2 is altered or down-regulated.