NOD1 and NOD2 Signaling in Infection and Inflammation

Abstract

Sensing intracellular pathogens is a process mediated by innate immune cells that is crucial for the induction of inflammatory processes and effective adaptive immune responses against pathogenic microbes. NOD-like receptors (NLRs) comprise a family of intracellular pattern recognition receptors that are important for the recognition of damage and microbial-associated molecular patterns. NOD1 and NOD2 are specialized NLRs that participate in the recognition of a subset of pathogenic microorganisms that are able to invade and multiply intracellularly. Once activated, these molecules trigger intracellular signaling pathways that lead to the activation of transcriptional responses culminating in the expression of a subset of inflammatory genes. In this review, we will focus on the role of NOD1 and NOD2 in the recognition and response to intracellular pathogens, including Gram-positive and Gram-negative bacteria, and on their ability to signal in response to non-peptidoglycan-containing pathogens, such as viruses and protozoan parasites.

Keywords: NOD1; NOD2; RIPK2; innate immunity; intracellular pathogens.

Figure 1

NOD1 and NOD2 signaling pathways and interaction partners. The canonical adaptor protein required for the activation of the signaling pathways downstream of NOD1 and NOD2 is the CARD-containing kinase RIPK2, a protein that interacts with NOD1 or NOD2 via homotypic CARD–CARD interactions leading to the activation of NF-κB and MAPKs. NOD/RIPK2 signaling can be inhibited by caspase-12 and/or A20. NOD1 and NOD2 proteins may also interact with the NLRP3 inflammasome, which leads to caspase-1 activation and IL-18 and IL-1β production. Viral ssRNA triggers a signaling pathway that is dependent on NOD2 and MAVS, leading to the activation of IRF3 and the induction of type I interferon. NOD1 and NOD2 activate the autophagy machinery through their interactions with ATG16L1 protein. Abbreviations include: NOD1, nucleotide-binding oligomerization domain 1; NOD2, nucleotide-binding oligomerization domain 2; RIPK2, receptor-interacting serine/threonine-protein kinase 2; CARD, caspase recruitment domain; JNK, c-Jun N-terminal kinases; TAK1, transforming growth factor-beta-activated kinase 1 TAK1; cIAP, inhibitor of apoptosis protein; NEMO, NF-κB essential modulator; IKK-γ, inhibitor of nuclear factor kappa-B kinase-gamma; IKK, I-kappa-B kinase; Ub, ubiquitinated; A20, ubiquitin-modified enzyme; ERK, extracellular-signal-regulated kinases; ASC, apoptosis-associated speck-like protein containing a CARD; IL-1β, interleukin-1; IL-18, interleukin-18; ssRNA, single-stranded RNA; MAVS, mitochondria anti-virus signaling protein; IFR3, interferon regulatory factor 3; Atg, autophagy-related gene; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κB. Specific Domains of NOD1 and NOD2 are indicated: NBD or NACHT (green rectangle); LRR (hatched rectangle); CARD (purple rectangle).