NOD2 Signaling Pathway
What is Nod2? Nod2 is a member of the NACHT family and one of two NOD proteins. It is a cytoplasmic receptor involved in signaling within the immune system. It is mostly expressed by two types of cells: Antigen Presenting Cells and Epithelial cells.
Nod2: 1040 Amino acid protein that has three different domains.
1. Two Card domains: Capase-recruitment domain
2. Nod domain: Nucleotide-binding oligomerization domain
3. LRR: Leucine Rich Repeat; site of ligand binding
Key Players (proteins) in NOD2 Pathway:
- Muramyl dipeptide (MDP) the ligand of NOD2
-NOD2 cycstolic/ receptor of MDP
-Receptor-interacting serine/threonine kinase (RICK)
-Inhibitor of NF-kB kinase complex (IKK g,a,b)
-inhibitor NF-kB (I kB)
-pro-inflammatory /anti-inflammatory cytokines and defensins
Scheme of pathway:
1. Muramyl dipeptide (MDP) in extracellular space from the cell walls of Gram positive and Gram negative Bacteria (present within the intestine)
2. MDP enters into the cell and Binds to NOD2.
3. MDP binding onto NOD2 causes a conformational change allowing a CARD-CARD interaction between RICK and NOD2
4. Activation of RICK upon binding with NOD2 allows polyubiquitylation of inhibitor of NF-kB (IkB) kinase g (IKKg). This is in complex with IKKa and IKKb.
5. Polyubiquitylation of inhibitor of NF-kB (IkB) kinase g (IKKg) leads to a phosphorolation event of IKKb.
6. The phosphorolation of IKKb leads to the phosphorolation of IkB. 6. a. This phosphorolation event leads to the dissociation of IkB from NF-kB.
6b. IkB goes onto be degraded by the proteosome.
7. NF-kB translocates into the nucleus.
Translocation then promotes transcription of many pro-inflammatory, anti-inflammatory cytokines and defensins. Some important cytokines are IL-1b, IL-8, IL-10 and a-defensins 5 and 6.
What is going on in CrohnÕs Disease involving NOD2? ŠNOD2 Mutations and Crohn's Disease
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