Abstract
The innate immune system plays a critical role in the early detection of pathogens, primarily by relying on pattern-recognition receptor (PRR) signaling molecules. Nucleotide-binding oligomerization domain 2 (NOD2) is a cytoplasmic receptor that recognizes invading molecules and danger signals inside the cells. Recent studies highlight the importance of NOD2′s function in maintaining the homeostasis of human body microbiota and innate immune responses, including induction of proinflammatory cytokines, regulation of autophagy, modulation of endoplasmic reticulum (ER) stress, etc. In addition, there is extensive cross-talk between NOD2 and the Toll-like receptors that are so important in the induction and tuning of adaptive immunity. Polymorphisms of NOD2′s encoding gene are associated with several pathological conditions, highlighting NOD2′s functional importance. In this study, we summarize NOD2′s role in cellular signaling pathways and take a look at the possible consequences of common NOD2 polymorphisms on the structure and function of this receptor.
Highlights
The innate immune system plays a critical role in the early detection of pathogens, primarily by relying on pattern-recognition receptor (PRR) signaling molecules
Autophagy-related 16-like 1 (ATG16L1) knockdown mice increased their level of cellular Nucleotide-binding oligomerization domain 2 (NOD2), suggesting that this critical autophagic protein can be involved in the regulation of NOD2 [45]
The results identified receptor-interacting serine/threonine-protein kinase 2 (RIPK2), autophagy related 16 like 1 (ATG16L1), caspase recruitment domain-containing protein 9 (CARD9), tumor necrosis factor receptor-associated factor 6 (TRAF6), and inhibitor of Nuclear Factor Kappa B Kinase Regulatory Subunit Gamma (IKBKG) as the highly connected molecules with NOD2 that are primarily involved in apoptosis and immune-related pathways (Figure S2)
Summary
NOD-like receptors (NLRs) are evolutionally conserved proteins, belonging to the PRR family [5]. NLRs are considered a large family of cytoplasmic receptors consisting of 22 members in humans and 34 members in mice [10] They have an important role in the triggering and development of innate immune responses thorough sensing intracellular danger signals [11]. NLR proteins share a conserved triple domain structure containing a C-terminal leucine-rich repeat (LRR) domain, a central nucleotide-binding and oligomerization domain (NOD/NBD) ( known as NACHT domain), and a N-terminal protein–protein interaction domain (Figure 1) [7]. The central NOD domain has ATPase and nucleotide binding activity, which is critical in protein oligomerization and function. The N-terminal effector domain is responsible for interacting with the downstream signaling molecules. NOD2 contains two tandem CARD effector domains and can interact with a wide variety of proteins containing the CARD domain (Figure 1) [12]. Mycobacterial N-glycolyl muramyl dipeptide and viral ssRNA are the ligands of NOD2, which can active their associated signaling pathways [2]
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