Insights into the molecular basis of the NOD2 signalling pathway

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.

Keywords: NLR; NOD1/2; RIP2 kinase; innate immunity; post-translational modification; signal transduction.

Figure 1.

The domain architecture of NOD1, NOD2 and RIP2. Exons are shown in alternating blue and green blocks. Protein domains as listed in the NCBI RefSeq database are shown in boxes (Accession numbers: NOD1—NP_006083; NOD2—NP_07115; RIP2—NP_003812). The length of each protein is shown. CARD, caspase recruitment domain; NACHT, NAIP, CIITA, HET-E and TP1-containing; LRR, leucine-rich repeats.

Figure 2.

NOD2-interaction partners influence a wide range of NOD2 functions. A schematic of the reported interactions between NOD2 and other cellular proteins. For the sake of simplicity, only a selection of proteins are displayed in direct contact with NOD2. Key NOD2 functional outputs are shown in black boxes. Protein partners influencing these functions directly are listed in the relevant location. Protein impacts on NOD2 are highlighted with coloured arrows. Proteins which exert their influence and interact with NOD2 at a predominantly membrane location are labelled in gold. Where the precise role of a protein partner is uncertain this is represented by a question mark, and the protein has been located in the most likely region of influence.

Figure 3.

Signal transduction downstream of RIP2. (a) MEKK4 and RIP2 form a complex preventing RIP2 ubiquitination. (b) In the presence of MDP, the MEKK4 : RIP2 complex dissociates and a NOD2 : RIP2 complex is able to form. (c) RIP2 is then ubiquitinated, leading to the recruitment of TAK1. (d) The IKK complex is recruited to RIP2 and IKKγ is ubiquitinated by TAK1. (e) IKKγ is then degraded by the proteasome, relieving inhibition of IKKα/β. (f) IKKα/β phosphorylates IκBα which subsequently releases p65 (g), which then enters the nucleus to enhance transcription of inflammatory cytokines.