Nod2: The intestinal gate keeper

Abstract

Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor that senses bacterial peptidoglycan (PGN)-conserved motifs in cytosol and stimulates host immune response. The association of NOD2 mutations with a number of inflammatory pathologies, including Crohn disease (CD), Graft-versus-host disease (GVHD), and Blau syndrome, highlights its pivotal role in host-pathogen interactions and inflammatory response. Stimulation of NOD2 by its ligand (muramyl dipeptide) activates pro-inflammatory pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs), and Caspase-1. A loss of NOD2 function may result in a failure in the control of microbial infection, thereby initiating systemic responses and aberrant inflammation. Because the ligand of Nod2 is conserved in both gram-positive and gram-negative bacteria, NOD2 detects a wide variety of microorganisms. Furthermore, current literature evidences that NOD2 is also able to control viruses' and parasites' infections. In this review, we present and discuss recent developments about the role of NOD2 in shaping the gut commensal microbiota and pathogens, including bacteria, viruses, and parasites, and the mechanisms by which Nod2 mutations participate in disease occurrence.

Fig 1. Mechanisms by which MDP enters into cells to trigger Nod2 signaling.

Several routes of MDP entry have been evidenced. Host cells can internalize MDP through either phagocytosis of whole bacteria, endocytosis, uptaking of PGN fragments from OMVs, or transmembrane channels such as hPepT1. A new way of Nod2 activation involving the entry of MDP via the apparatus secretion system of bacteria has recently been described. NOD2 activation requires its location to be in the vicinity of the site of MDP delivery. Two peptide transporters (SLC15A3 and SLC15A4) are able to translocate MDP toward the cytosolic compartment. NOD2 protein exhibits three domains, including caspase activation and recruitment domains (CARDs), nucleotide-binding oligomerization domain (NOD), and leucine-rich repeat (LRR). The NOD module contains a nucleotide-binding domain (NBD), a winged helix (WH), and two helix domains (HD1 and HD2). The interaction between NBD and WH, important to stabilize Nod2 in an inactive form, is maintained by adenosine diphosphate (ADP)-mediated packed conformation. Upon ligand binding, HD2 mediates conformational changes of the NBD, WH, and HD1 to allow ADP-ATP exchange, self-oligomerization, and downstream signaling. The effector CARDs mediate intracellular signaling after interaction between the LRR domain and MDP. NOD2 oligomerization induces a signaling complex named nodosome. NOD2 attracts receptor-interacting serine/threonine-protein kinase 2 (RIP2) via a CARD–CARD homotypic interaction, followed by transforming growth factor beta-activated kinase 1 (TAK1) and TAK1 binding proteins 2 and 3 (TAB2 and TAB3). This complex induces the activation of both MAPKs and NF-κB pathways. The interaction of NOD2 with other partners, including Caspase-1 and ATG16L1, results in IL-1β secretion and autophagy, respectively.