Abstract
The cytosolic pattern recognition receptor NOD2 is activated by the peptidoglycan fragment muramyl dipeptide to generate a proinflammatory immune response. Downstream effects include the secretion of cytokines such as interleukin 8, the upregulation of pro-interleukin 1β, the induction of autophagy, the production of antimicrobial peptides and defensins, and contributions to the maintenance of the composition of the intestinal microbiota. Polymorphisms in NOD2 are the cause of the inflammatory disorder Blau syndrome and act as susceptibility factors for the inflammatory bowel condition Crohn's disease. The complexity of NOD2 signalling is highlighted by the observation that over 30 cellular proteins interact with NOD2 directly and influence or regulate its functional activity. Previously, the majority of reviews on NOD2 function have focused upon the role of NOD2 in inflammatory disease or in its interaction with and response to microbes. However, the functionality of NOD2 is underpinned by its biochemical interactions. Consequently, in this review, we have taken the opportunity to address the more ‘basic’ elements of NOD2 signalling. In particular, we have focused upon the core interactions of NOD2 with protein factors that influence and modulate the signal transduction pathways involved in NOD2 signalling. Further, where information exists, such as in relation to the role of RIP2, we have drawn comparison with the closely related, but functionally discrete, pattern recognition receptor NOD1. Overall, we provide a comprehensive resource targeted at understanding the complexities of NOD2 signalling.
Highlights
Nucleotide-binding and oligomerization-domain containing 2 (NOD2) was the second member of the nucleotide-binding domain and leucine-rich repeat containing receptor (NLR) family to be identified [1], following the discovery of NOD1 in 1999 [2]
Based on the recent structure of NLRC4 [3] (PDB ID: 4KXF), it can be predicted that the NACHT domains in NOD1 and NOD2 are followed by a proximal helical domain (HD1), a winged-helix domain (WH) and a distal helical domain (HD2)
Wagner et al [37] showed that E69K and D70K mutants disrupt receptor-interacting protein 2 (RIP2) binding in a yeast two-hybrid study, whereas Fridh et al [68] generated the E69K and E72K mutants in E. coli constructs and found that they are not necessary for RIP2 binding, instead proposing that a basic patch on NOD2 CARDa interacts with an acidic patch on the RIP2 caspase recruitment domain (CARD)
Summary
The cytosolic pattern recognition receptor NOD2 is activated by the peptidoglycan fragment muramyl dipeptide to generate a proinflammatory immune response. The complexity of NOD2 signalling is highlighted by the observation that over 30 cellular proteins interact with NOD2 directly and influence or regulate its functional activity. The majority of reviews on NOD2 function have focused upon the role of NOD2 in inflammatory disease or in its interaction with and response to microbes. We have focused upon the core interactions of NOD2 with protein factors that influence and modulate the signal transduction pathways involved in NOD2 signalling. Where information exists, such as in relation to the role of RIP2, we have drawn comparison with the closely related, but functionally discrete, pattern recognition receptor NOD1. We provide a comprehensive resource targeted at understanding the complexities of NOD2 signalling
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