NOD2

NOD2 Full Name

nucleotide-binding oligomerization domain containing 2

NOD2 Introduction

NOD2 is a crucial cytosolic pattern recognition receptor (PRR) primarily expressed in immune cells—such as macrophages and dendritic cells—as well as in intestinal epithelial cells. It recognizes muramyl dipeptide (MDP), a conserved motif derived from bacterial peptidoglycan (PGN). The protein structure of NOD2 comprises three key functional domains: a C-terminal leucine-rich repeat (LRR) region responsible for MDP recognition, a central NOD domain that mediates self-oligomerization, and an N-terminal caspase activation and recruitment domain (CARD) that initiates downstream signaling. Upon MDP binding to the LRR region, NOD2 undergoes a conformational change and oligomerizes, thereby exposing its CARD domain. This enables the specific recruitment of the downstream adaptor protein RIP2 (RICK/RIPK2) via CARD–CARD interactions, forming a signal transduction complex. Additionally, NOD2 can directly interact with the key autophagy protein ATG16L1, integrating antibacterial autophagy with innate immune signaling and establishing a central hub for host defense.

The NOD2–RIP2 axis serves as the core pathway linking pathogen recognition to inflammatory responses. Upon activation by MDP, the recruited RIP2 undergoes K63-linked polyubiquitination, leading to the activation of the TAK1 complex. This subsequently phosphorylates the IκB kinase (IKK) complex and mitogen-activated protein kinases (MAPKs), ultimately driving the nuclear translocation of transcription factors NF-κB and AP-1. These events induce the expression of pro-inflammatory cytokines—such as TNF-α, IL-6, and IL-8—as well as antimicrobial peptides like β-defensins. This process not only contributes directly to the clearance of intestinal pathogens—including Salmonella Typhi and Listeria—but also helps maintain intestinal mucosal homeostasis by regulating the composition of the microbiota.

Figure 1. Mechanisms by which MDP enters into cells to trigger Nod2 signaling. (Source: Al Nabhani Z, et al. 2017)

Simultaneously, the interaction between NOD2 and ATG16L1 represents a non-canonical function: ATG16L1 binds to NOD2 via its WD40 domain, promoting bacteria-induced autophagosome formation and antigen presentation. This interaction also negatively regulates K63-linked ubiquitination of RIP2, thereby curbing excessive NF-κB activation. This dual regulatory mechanism ensures both precision in antibacterial defense and timely resolution of inflammation. Notably, loss of ATG16L1 leads to uncontrolled RIP2 signaling and exacerbates intestinal inflammation. Loss-of-function mutations in NOD2 represent one of the most significant genetic risk factors for Crohn's disease (CD). In contrast, gain-of-function mutations in NOD2 cause rare monogenic autoinflammatory disorders—Blau syndrome (BS) and early-onset sarcoidosis (EOS). Missense mutations within the CARD domain result in ligand-independent, persistent oligomerization and hyperactivation of NF-κB, leading to the classic triad of granulomatous arthritis, skin rash, and uveitis.

Alternate Names for NOD2

NOD2; nucleotide-binding oligomerization domain containing 2

• 1. Al Nabhani Z, et al. Nod2: The intestinal gate keeper. PLoS Pathog. 2017 Mar 2;13(3):e1006177.
  2. Negroni A, et al. NOD2 and inflammation: current insights. J Inflamm Res. 2018 Feb 12;11:49-60.