NOD1, NOD2, and NLRC5 Receptors in Antiviral and Antimycobacterial Immunity

Abstract

The innate immune system recognizes pathogen-associated molecular motifs through pattern recognition receptors (PRRs) that induce inflammasome assembly in macrophages and trigger signal transduction pathways, thereby leading to the transcription of inflammatory cytokine genes. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) represent a family of cytosolic PRRs involved in the detection of intracellular pathogens such as mycobacteria or viruses. In this review, we discuss the role of NOD1, NOD2, and NLRC5 receptors in regulating antiviral and antimycobacterial immune responses by providing insight into molecular mechanisms as well as their potential health and disease implications.

Keywords: NLR; antimicrobial immunity; ssRNA virus.

Figure 1

NOD1 and NOD2 signaling pathway. Gamma-glutamyl diaminopimelic acid (iE-DAP) and muramyl dipeptide (MDP) activate the nucleotide-binding oligomerization domains 1/2 (NOD1) and (NOD2), respectively. Activation of NODs leads to the recruitment of receptor-interacting serine/threonine kinase (RIP2). In the next step, activated RIP2 can lead to ubiquitination of the essential modulator of NF-κB (NEMO) and activation of the IKK (IκB kinase) complex. The activated IKK complex phosphorylates the inhibitor of kappaB (IκBα). The activated IKK complex phosphorylates the kappaB inhibitor (IκBα), leading to the release of NF-κB, which, after translocation to the cell nucleus, binds to kappaB (κB) elements, thereby activating pro-inflammatory cytokines. NOD1 and NOD2 also activate mitogen-activated protein kinases (MAPKs), such as p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). NOD1 and NOD2 also interact with the NLRP3 inflammasome, which leads to caspase-1 activation and IL-18 and IL-1β production. Activation of NOD1 and NOD2 results in the formation of a TBK1 and the inhibitor of the nuclear factor kappaB kinase (IKKε) complex, which leads to the expression of type I IFNs. As well, through the interaction of NOD2 with mitochondrial antiviral signaling protein MAVS, the expression of IFN I genes occurs.

Figure 2

NLRC5 signaling pathway. As a result of the interaction of NOD-like receptor C5 NLRC5 with IκB kinase alpha/beta (IKKα/β), the NEMO IKKα/β complex is not formed and nuclear factor kappa B (NF-κB) expression is stopped. The interaction of NLRC5 with mitochondrial antiviral signaling protein (MAVS) and RIG-I leads to the formation of a complex of NLRC5 plus MAVS and RIG-I, which contributes to the expression of IFN I. Overexpression of NLCR5 activates caspase 1 (CASP1), which converts pro-IL-1β to active IL-1β.