Roles of NOD1 (NLRC1) and NOD2 (NLRC2) in innate immunity and inflammatory diseases

Abstract

NOD1 {nucleotide-binding oligomerization domain 1; NLRC [NOD-LRR (leucine-rich repeat) family with CARD (caspase recruitment domain) 1]} and NOD2 (NLRC2) are among the most prominent members of the NLR (NOD-LRR) family -proteins that contain nucleotide-binding NACHT domains and receptor-like LRR domains. With over 20 members identified in humans, NLRs represent important components of the mammalian innate immune system, serving as intracellular receptors for pathogens and for endogenous molecules elaborated by tissue injury. NOD1 and NOD2 proteins operate as microbial sensors through the recognition of specific PG (peptidoglycan) constituents of bacteria. Upon activation, these NLR family members initiate signal transduction mechanisms that include stimulation of NF-κB (nuclear factor-κB), stress kinases, IRFs (interferon regulatory factors) and autophagy. Hereditary polymorphisms in the genes encoding NOD1 and NOD2 have been associated with an increasing number of chronic inflammatory diseases. In fact, potential roles for NOD1 and NOD2 in inflammatory disorders have been revealed by investigations using a series of animal models. In the present review, we describe recent experimental findings associating NOD1 and NOD2 with various autoimmune and chronic inflammatory disorders, and we discuss prospects for development of novel therapeutics targeting these NLR family proteins.

Figure 1. Major NOD-dependent signalling pathways

(A) NF-κB and AP-1 pathways. Bacterial PG-derived peptides γ-D-glutamyl-m-diaminopimelic acid (iE-DAP) and MDP are recognized by the cytosolic receptors NOD1 and NOD2. These ligands bind to NOD1 or NOD2 through the LRR domain of these molecules. This interaction initiates the activation of NOD1 and NOD2 due to the induction of a complex conformational change that results in protein oligomerization and further interaction with downstream effectors. NOD1 or NOD2 assembly recruits RIP2 through CARD–CARD interactions, resulting in RIP2 ubiquitination by IAPs and recruitment of LUBAC complex by XIAP, with further binding of the TAB1/TAK1 complex. It is believed that TAK1 gets activated through autophosphorylation and stimulates downstream IKK complex, including Lys⁶³-linked polyubiquitination of NEMO (IKKγ), the regulatory subunit of the IKK complex, which also consists of the catalytic subunits IKK1 (IKKα) and IKK2 (IKKβ). This event is followed by IKK2 phosphorylation, which further phosphorylates the NF-κB inhibitor IκBα. IκBα is then ubiquitinated by the SCF/β-TrCP complex and further degraded by 26S proteasome. The degradation of IκBα releases NF-κB dimers to translocate into the nucleus, where they up-regulate target genes involved in host defence and apoptosis. NOD oligomerization and further RIP2 activation also recruits TAB/TAK1 complexes to mediate the phosphorylation of MAPKs, such as JNK, ERK and p38 MAPK, through the upstream activation of MKKs. These kinases translocate to the nucleus and then phosphorylate AP-1 transcription factors (c-fos, c-Jun, ATF and JDP family members) to mediate expression of target genes containing a TRE (TPA DNA-response element). (B) MAVS/IRF pathway. Activation of both NOD1 and NOD2 by bacterial products induces receptor oligomerization and RIP2 recruitment, which in turn binds TRAF3 and induces TBK1/IKKϵ activation through a mechanism that is not completely understood. This is followed by IRF transcription factor dimerization and activation, resulting in binding to and induction of type I IFN genes. Similarly, virus-derived single-stranded RNA binds NOD2 and induces its association with mitochondrial receptor MAVS, resulting in the activation of IRF3 transcription factors and induction of type I IFNs. TRAF3 also directly binds MAVS but its precise role requires further investigation.