Function of Nod-like receptors in microbial recognition and host defense

Abstract

Nucleotide oligomerization domain (NOD)-like receptors (NLRs) are a specialized group of intracellular proteins that play a critical role in the regulation of the host innate immune response. NLRs act as scaffolding proteins that assemble signaling platforms that trigger nuclear factor-kappaB and mitogen-activated protein kinase signaling pathways and control the activation of inflammatory caspases. Importantly, mutations in several members of the NLR family have been linked to a variety of inflammatory diseases consistent with these molecules playing an important role in host-pathogen interactions and the inflammatory response. In this review, we focus on the role of Nod1 and Nod2 in host defense and in particular discuss recent finding regarding the role of Nlrc4, Nlpr1, and Nlrp3 inflammasomes in caspase-1 activation and subsequent release of proinflammatory cytokines such as interleukin-1 beta.

Fig. 1. Schematic representation of the Nod2 signaling pathway

The NLR Nod2 recognizes bacterial PGN fragments such as MDP and activates NF-κB and MAPK signaling via the indicated proteins leading to the transcriptional upregulation of a variety of proinflammatory cytokines and antimicrobial peptides. Negative feedback regulation occurs upon induction of the deubiquitanase A20. The posttranslational regulation of various components of the pathway is indicated by green circles (phosphorylation) and red or blue circles (ubiquitination). In the case of RICK, K63-mediated polyubiquitination at K209 is essential for recruitment of Tak1. For NEMO, K48-mediated ubiquitination at residue K399 targets it for proteasome-dependent degradation. K63-linked polyubiquitination at amino acid K285 is important for complex formation with RICK (48).

Fig. 2. The two step model for the induction and maturation of the proinflammatory cytokine IL-1β during the innate immune response

(A) In the absence of NLR signals, TLR signaling (Signal 1) leads to the upregulation of pro-IL-1β transcription. (B) In response to a variety of intracellular signals (Signal 2) such as bacterial ligands and endogenous danger signals, NLRs are released from their auto-inhibited monomeric conformation leading to the assembly of a function inflammasome capable of activating the cysteine protease caspase-1. Active caspase-1 catalyzes the proteolytic processing of proIL-1β (and IL-18 not shown) into active cytokines that are then released from the cell.

Fig. 3. Schematic representation of the multi-domain architectures of various NLRs and their assembly into a functional inflammasome

Apaf-1 is a multi-domain scaffolding protein critical for the assembly of the apoptosome (not shown), a multi-protein complex critical for mediating apoptotic cell death. Subsequently, several NLR proteins were identified as Apaf-1-related molecules based on similar domain architectures (A). In response to various intracellular stimuli including microbial moieties and endogenous products released by dying cells, NLRs are released from their auto-inhibited monomeric conformation and act as molecular scaffolds to assemble multi-protein complexes known as inflammasomes. Assembly of the inflammasome leads to caspase-1 activation and proteolytic processing of proinflammatory cytokines such as IL-1β (B). In this review we focus on three of the best characterized inflammasomes: Ipaf1, Nalp3, and Nalp1.