NOD-like receptors (NLRs): bona fide intracellular microbial sensors

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The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) (nucleotide-binding domain leucine-rich repeat containing) family of proteins has been demonstrated to function as regulators of innate immune response against microbial pathogens. Stimulation of NOD1 and NOD2, two prototypic NLRs, results in the activation of MAPK and NF-κB. On the other hand, a different set of NLRs induces caspase-1 activation through the assembly of an inflammasome. This review discusses recent findings regarding the signaling pathways utilized by NLR proteins in the control of caspase-1 and NF-κB activation, as well as the nonredundant role of NLRs in pathogen clearance. The review also covers advances regarding the cellular localization of these proteins and the implications this may have on pathogen sensing and signal transduction.

Introduction

Nearly 20 years ago, Charles Janeway coined the term pathogen associate molecular pattern (PAMP) to define the essential chemical determinants broadly expressed on different classes of pathogens that could interact with pattern recognition receptors (PRRs) on ‘innate’ cells of the immune system and activate them for the initiation of immune functions. Since then, a number of different PRRs have been discovered and demonstrated to sense a wide range of PAMPs, such as lipopolysaccharides (LPSs), peptidoglycan (PGN), flagellin, and microbial nucleic acids. PRRs can be found in the extracellular space, integrated in cellular membranes or in the cytosol. Perhaps the best-known PRRs are the Toll-like receptors (TLRs), which are localized either at the cell surface or within endosomes [1]. Cytoplamic PRRs include RIG-1 and MDA-5, which are found in the cytosol and are involved in viral recognition [1], and the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family [2]. Our substantial understanding of how PAMPs interact with PRRs to promote host immune defense can be attributed to research in the field of TLR biology. However, in recent years, there is an emerging functional role of NLRs in complementing and synergizing with TLRs in innate immunity. NLR orthologs can be found in plants (R genes), which are required for antipathogen response in plants. Given the importance of R-proteins in plant cell defense, one could hypothesize that mammalian NLRs are functionally analogous to plant R-proteins.

Section snippets

NOD-like receptors

The NOD domain was first found in apoptotic protease activating factor 1 (APAF1) and its nematode homolog CED-4, which are regulators of developmental and p53-dependent programmed cell death [3, 4]. Subsequently, two NOD-containing molecules, NOD1 (caspase recruitment domain 4, CARD4) and NOD2 (CARD15), were identified through database searches for APAF1/CED-4 homologs. At present, the human NLR family is composed of 23 proteins, and there are at least 34 NLR genes in mice. Although primarily

NOD1 and NOD2 activation and signaling

NOD1 and NOD2 can be viewed as the ‘germinal’ and the most well-studied members of the NLR family [9, 10]. NOD1 is ubiquitously expressed, while NOD2 expression is restricted to monocytes, macrophages, dendritic cells, and intestinal Paneth cells [2]. Initial biochemical characterization of NOD1 and NOD2 revealed that both NOD1 and NOD2 induced NF-κB activation in a TLR-independent fashion [9]. Subsequent analysis demonstrated that NOD1 and NOD2 recognize different structural core motifs

Cellular localization of NOD1 and NOD2

Despite very low expression of endogenous proteins, in vitro enforced protein expression of NLRs has shed some light on the intracellular distribution of these molecules. In addition to their cytosolic localization, both NOD1 and NOD2 were also found to be associated with the plasma membrane [29, 30•]. The plasma membrane association of NOD1 and NOD2 has been linked to the activation of downstream signaling events since point-mutations of NOD1 and NOD2 that interfered with their capacity to

NLRs and the inflammasome

In addition to activating NF-κB and MAPK, NLRs are also involved in the formation of the ‘inflammasome’. The inflammasome is a signaling platform scaffolded by NLR proteins and mediates the activation of caspase-1, which is required for the processing and maturation of the proinflammatory cytokines, IL-1β and IL-18. To date there are three known NLRs that participate in the formation of inflammasome complexes: NLRP1, NLRP3, and NLRC4. Common to these inflammasomes is the role of ASC as the

Concluding remarks

In the past few years, many discoveries have been made in the field of NLRs regarding the functional roles of these proteins in innate immunity. Yet the question of how NLRs ‘sense’ their ‘ligands’ remains to be fully elucidated. Despite the similarities between NLRs and other LRR-containing pathogen-recognition molecules, there is a scarcity of evidence to support that NLRs directly bind and/or recognize pathogens or pathogen-derived products. The presence of LRRs in NLRs, analogous to

References and recommended reading

Paper of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

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