Abstract
Polymorphisms in NOD2 represent the single greatest genetic risk factor for the development of Crohn’s disease. Three different non-synonomous NOD2 polymorphisms – R702W, G908R, and L1007fsincC – account for roughly 80% of all NOD2-associated cases of Crohn’s disease and are reported to result in a loss of receptor function in response to muramyl dipeptide (MDP) stimulation. Loss of NOD2 signaling can result from a failure to detect ligand; alterations in cellular localization; and changes in protein interactions, such as an inability to interact with the downstream adaptor protein RIPK2. Using an overexpression system, we analyzed ~50 NOD2 polymorphisms reportedly connected to Crohn’s disease to determine if they also displayed loss of function and if this could be related to alterations in protein localization and/or association with RIPK2. Just under half the polymorphisms displayed a significant reduction in signaling capacity following ligand stimulation, with nine of them showing near complete ablation. Only two polymorphisms, R38M and R138Q, lost the ability to interact with RIPK2. However, both these polymorphisms still associated with cellular membranes. In contrast, L248R, W355stop, L550V, N825K, L1007fsinC, L1007P, and R1019stop still bound RIPK2, but showed impaired membrane association and were unable to signal in response to MDP. This highlights the complex contributions of NOD2 polymorphisms to Crohn’s disease and reiterates the importance of both RIPK2 binding and membrane association in NOD2 signaling. Simply ascertaining whether or not NOD2 polymorphisms bind RIPK2 or associate with cellular membranes is not sufficient for determining their signaling competency.
Highlights
Nucleotide oligomerization domain 2 (NOD2) is a cytoplasmic pattern recognition receptor that has been connected with a variety of inflammatory disorders including Crohn’s disease, Blau syndrome, asthma, sarcoidosis, and arthritis [1]
NOD2 is organized into three primary functional domains: an Nterminal effector region consisting of two caspase activation domains (CARDs); a central nucleotide-binding domain; and a C-terminal series of leucine-rich repeats (LRRs)
At the outset of this study, 98 single nucleotide polymorphism (SNP) in NOD2 associated with either Blau Syndrome or Crohn’s disease were identified using published data [5, 6, 13,14,15,16,17,18] and the NCBI database of NOD2 SNPs
Summary
Nucleotide oligomerization domain 2 (NOD2) is a cytoplasmic pattern recognition receptor that has been connected with a variety of inflammatory disorders including Crohn’s disease, Blau syndrome, asthma, sarcoidosis, and arthritis [1]. NOD2 is organized into three primary functional domains: an Nterminal effector region consisting of two caspase activation domains (CARDs); a central nucleotide-binding domain; and a C-terminal series of leucine-rich repeats (LRRs). Formation of the active signaling complex, most likely occurs at cellular membranes and signal propagation requires interaction with specific adaptor proteins. This primarily involves CARD-mediated interaction with the adaptor kinase receptor-interacting protein kinase 2 (RIPK2), but other proteins, such as CARD9 and TRAF4, can be involved. This stimulates a pro-inflammatory immune response via nuclear factor kappa B (NFκB) and mitogen-associated protein kinase (MAPK) pathways
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