NOD1 and NOD2: Essential Monitoring Partners in the Innate Immune System

Abstract

Nucleotide-binding oligomerization domain containing 1 (NOD1) and NOD2 are pivotal cytoplasmic pattern-recognition receptors (PRRs) that exhibit remarkable evolutionary conservation. They possess the ability to discern specific peptidoglycan (PGN) motifs, thereby orchestrating innate immunity and contributing significantly to immune homeostasis maintenance. The comprehensive understanding of both the structure and function of NOD1 and NOD2 has been extensively elucidated. These receptors proficiently recognize an array of damage-associated molecular patterns (DAMPs) as well as pathogen-associated molecular patterns (PAMPs), subsequently mediating inflammatory responses and autophagy. In recent years, emerging evidence has highlighted the crucial roles played by NOD1 and NOD2 in regulating infectious diseases, metabolic disorders, cancer, and autoimmune conditions, among others. Perturbation in either their loss or excessive activation can detrimentally impact immune homeostasis. This review offers a comprehensive overview of the structural characteristics, subcellular localization, activation mechanisms, and significant roles of NOD1 and NOD2 in innate immunity and related disease.

Keywords: NOD1; NOD2; inflammatory response; innate immunity.

Figure 1

Structures of NLRs. Human and mouse NLRs are classified into five distinct subgroups based on their N-terminal domains: NLRA contains an acidic transactivating domain (AD); NLRB, also known as NAIPs, which contains a baculovirus inhibitor of apoptosis protein repeat (BIR); NLRC, which contains a caspase activation and recruitment domain (CARD); NLRP, which contains a pyrin domain (PYD); and NLRX, which possesses a unique domain with no similarity to known NLR subfamily members. NLRC1 and NLRC2 are commonly referred to as NOD1 and NOD2, respectively. Abbreviations: CIITA: MHC class II transcription activator; FIIND: autoproteolytic domain; LRR: leucine rich repeat; NAIP: NLR family apoptosis inhibitory protein; PST, proline/serine/threonine.

Figure 2

Basic structure of NOD1 and NOD2. During the resting state, the chaperone HSP70 or HSP90 stabilizes the LRR of NOD1 and NOD2, while the bent LRRs cover the NACHT domain. Upon ligand stimulation, LRR expends to recognize the ligand, leading to a transition from an autoinhibitory state to a semi-open conformation and exposing the NACHT domain. Subsequently, a nucleotide-catalyzed reaction (from ADP to ATP) occurs in the NBD domain, resulting in oligomerization of NOD molecules and recruitment of downstream effector molecules for signal transduction. Finally, ATP hydrolysis leads to inactivation and reset of the signaling platform. Abbreviations: HSP 70: heat shock protein 70; HSP 90: heat shock protein 90; CARD: caspase activation and recruitment domain; LRR: leucine rich repeat; NBD: nucleotide-binding domain; HD1: helical domain 1; HD2: helical domain 1; WHD: the winged-helix domain; MDP: muramyl dipeptide; iE-DAP: γ-D-glutamyl-meso-diaminopimelic acid dipeptide.

Figure 3

Mechanisms of NOD1 and NOD2 ligands delivery. Macrophages can phagocytose bacteria, leading to the activation of NOD1 and NOD2 in the cytoplasm upon lysosomal degradation of phagosomes. Furthermore, intracellular replication of certain pathogens can also trigger the activation of NOD1 and NOD2. In the extracellular matrix, PGNs are internalized into cells through endocytosis and subsequently delivered to NOD1 and NOD2 with the assistance of endosomal membrane transporter SLC15A3/4. Different bacterial species possess distinct secretion systems that enable direct delivery of pathogens into host cells. Additionally, Gram-negative bacteria release outer membrane vesicles, while Gram-positive bacteria like Staphylococcus aureus release membrane vesicles containing PGNs, which are internalized by cells to activate NOD1 and NOD2.

Figure 4

NOD1- and NOD2-mediated signaling pathway. PGN directly activates classical inflammatory pathways mediated by NOD1 and NOD2, including the NF-κB signaling pathway and MAPK signaling pathway, subsequently leading to the activation of nuclear transcription factors NF-κB and AP-1, thereby inducing the production of pro-inflammatory cytokines. Autophagy can be modulated by NOD1 and NOD2 through the activation of the ATG16L1/ATG12/ATG5 triad complex, ultimately resulting in phagosome formation. There exists an antagonistic relationship between autophagy and inflammatory pathways. Upon recognition of ssRNA, NOD2 collaborates with mitochondrial MAVs to trigger the IRF3 pathway. Both NOD1 and NOD2 play a role in maintaining cellular homeostasis. Endoplasmic reticulum stress activates inflammatory pathways mediated by NOD1 and NOD2, which are associated with IRE1α; however, the specific mechanism remains unknown. The involvement of S1P in this process is yet to be elucidated.