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EcoSal Plus

Domain 8:

Pathogenesis

NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins

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  • Authors: Leticia A. M. Carneiro1, JÖrg H. Fritz2, Thomas A. Kufer3, Leonardo H. Travassos4, Szilvia Benko5, and Dana J. Philpott6
  • Editor: Michael S. Donnenberg7
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Laboratory Medicine and Pathobiology; 2: Departments of Immunology; 3: University of Toronto, Toronto, Ontario M5S 1A8, Canada, and Molecular Innate Immunobiology Group, Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50931 Cologne, Germany; 4: Departments of Immunology; 5: Laboratory Medicine and Pathobiology; 6: Departments of Immunology; 7: University of Maryland, School of Medicine, Baltimore, MD
  • Received 09 February 2009 Accepted 03 May 2009 Published 07 December 2009
  • Address correspondence to Dana J. Philpott dana.philpott@utoronto.ca
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  • Abstract:

    Eukaryotes have evolved strategies to detect microbial intrusion and instruct immune responses to limit damage from infection. Recognition of microbes and cellular damage relies on the detection of microbe-associated molecular patterns (MAMPs, also called PAMPS, or pathogen-associated molecular patterns) and so-called "danger signals" by various families of host pattern recognition receptors (PRRs). Members of the recently identified protein family of nucleotide-binding domain andleucine-rich-repeat-containing proteins (NLR), including Nod1, Nod2, NLRP3, and NLRC4, have been shown to detect specific microbial motifs and danger signals for regulating host inflammatory responses. Moreover, with the discovery that polymorphisms in , , , and are associated with susceptibility to chronic inflammatory disorders, the view has emerged that NLRs act not only as sensors butalso can serve as signaling platforms for instructing and balancing host immune responses. In this chapter, we explore the functions of these intracellular innate immune receptors and examine their implication in inflammatory diseases.

  • Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3

Key Concept Ranking

Major Histocompatibility Complex Class II
0.4151014
Bacterial Proteins
0.40033635
Tumor Necrosis Factor alpha
0.34594864
0.4151014

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ecosalplus.8.8.3.citations
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/content/journal/ecosalplus/10.1128/ecosalplus.8.8.3
2009-12-07
2017-07-21

Abstract:

Eukaryotes have evolved strategies to detect microbial intrusion and instruct immune responses to limit damage from infection. Recognition of microbes and cellular damage relies on the detection of microbe-associated molecular patterns (MAMPs, also called PAMPS, or pathogen-associated molecular patterns) and so-called "danger signals" by various families of host pattern recognition receptors (PRRs). Members of the recently identified protein family of nucleotide-binding domain andleucine-rich-repeat-containing proteins (NLR), including Nod1, Nod2, NLRP3, and NLRC4, have been shown to detect specific microbial motifs and danger signals for regulating host inflammatory responses. Moreover, with the discovery that polymorphisms in , , , and are associated with susceptibility to chronic inflammatory disorders, the view has emerged that NLRs act not only as sensors butalso can serve as signaling platforms for instructing and balancing host immune responses. In this chapter, we explore the functions of these intracellular innate immune receptors and examine their implication in inflammatory diseases.

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Figures

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Figure 1

NOD-like receptors (NLRs) are characterized by three distinct domains: an N-terminal effector domain, being either a pyrin (PYD), a CARD (caspase activation and recruitment domain), or a BIR (baculovirus IAP [inhibitor of apoptosis] repeat) domain; a central NACHT domain (domain present in IP [neuronal apoptosis inhibitor protein], IITA [major histocompatibility complex class II transactivator], ET-E [plant gene product involved in vegetative incompatibility], P-1 [telomerase-associated protein 1]) which is common to all NLR members and in many cases extended by a helical NACHT-associated domain (NAD); and a C-terminal leucine-rich repeats (LRR) domain, which is thought to constitute the microbial-sensing portion of the molecule. Both NACHT and NAD domains are key features of a recently defined STAND (signal transduction ATPase with numerous domains) family of P-loop NTPases, which are distantly related to AAA+ ATPases (ATPases associated with diverse cellular activities). The NACHT and NAD domains are homologous to domains of related proteins, the proapoptotic regulators such as APAF-1 (apoptotic protease-activating factor-1) in mammals, CED-4 ( death protein 4) in nematodes, and disease resistance genes encoding R-proteins in plants such as RPS4 (). The CARD and PYD counterparts in plants are coiled coil (CC) and Toll/interleukin-1 receptor (TIR) domains. Pyrin, which is related to the other PYD containing NLRs and similarly implicated in fever-related disorders, also comprises a zinc finger B-box (zf-B-box), a dual-specificity kinase SplA and ryanodine receptor domain (SPRY), and a SPRY-associated (PRY) domain in addition to PYD. Finally, a schematic representation of adaptors involved in NLR-signaling such as Rip2 (receptor-interacting protein 2), ASC (apoptosis-associated speck-like protein containing a CARD domain), and CARDINAL (CARD-inhibitor of NF-κB-activating ligand) is outlined. FIIND, function to find; AD, activation domain.

Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3
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Figure 2

Peptidoglycan is a polymer of alternating -acetylglucosamine (NAG) and -acetylmuramic (NAM) linked by peptide bridges. A lysine residue is present in the peptidoglycan of most gram-positive bacteria (Lys-PGN), and a meso-diaminopimelic acid in the peptidoglycan of most gram-negative bacteria (DAP-PGN). With regard to DAP-PGN, green shows the naturally occurring substructure recognized by human Nod1, while the motif favored by murine Nod1 is blue. The minimal structure recognized by Nod1 is the amino acid -Glu-meso-DAP (also known as iE-DAP), outlined in red. Gray in both DAP-PGN and Lys-PGN refers to the common motif, muramyl dipeptide, recognized by Nod2. Within Lys-PGN, the substructure in pink is also a trigger of Nod2.

Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3
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Figure 3

The Nod1 ligand is sensed in the cytosol of the cell, either indirectly or directly by the LRR domain of Nod1. The protein then oligomerizes through the NBD, recruiting Rip2, a kinase that leads to the activation of NF-κB (mainly the p50/p65 component) through TAK1. Nod1 triggering also activates ERK/p38 and JNK signaling. Nod1 triggers caspase 8 (if the cells are coincubated with cycloheximide), which can lead to apoptosis, and caspase 12, an amplifier of the inflammatory response. Designated in red are the proteins that have been shown to interact with Nod1 or other components of the pathway to modify signaling, either positively or negatively.

Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3
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Figure 4

The Nod2 ligand MDP triggers Nod2 oligomerization and subsequent recruitment and activation of Rip2 and TAK1, leading to activation of the canonical NF-κB pathway. Through NIK, Nod2 can also activate the noncanonical NF-κB pathway leading to the activation of NF-κB composed of RelB/p52. In conjunction with TLR signaling, this pathway has been shown to be required for induction of BLC (B-lymphocyte chemokine, also known as CXCL13). Triggering of Nod2 activates ERK/p38 and JNK signaling. Nalp3 induction and subsequent processing of pro-IL-1β is in some cases triggered by MDP, but may or may not require Nod2 (see text). Shown in red are proteins that positively or negatively regulate Nod2 function. Grim19 is an associated regulator that may be required for NF-κB induction. Rac1 may help tether Nod2 to the membrane via Erbin.

Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3
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Figure 5

NLRP1, NLRP3, and NLRC4 can form functional “inflammasomes” that interact with caspase-1 and lead to the processing of proforms of IL-1β, IL-18, IL-33, and possibly other secreted effectors. Inflammasome activation requires a “double hit,” in that the target cell must be first prestimulated with TLR or perhaps Nod1/Nod2 ligands to upregulate gene expression of NF-κB-dependent, caspase-1 targets, including pro-IL-1β. The second “hit” is activation of the particular NLR by (a) a microbial signal, MDP or lethal toxin in the case of NLRP1 and bacterial toxins, or bacterial or viral nucleic acids in the case of NLRP3, or flagellin in the case of NLRC4, or (b) a danger signal, which can include xenogenous particles or host-derived danger signals (see Table 2 ). ROS production, potassium efflux from the cell, or lysosomal damage may be the common effector of these triggers that lead to inflammasome activation. ASC, an adaptor molecule, seems to be required for caspase-1 activation but not cell death. Naip5 (in mice) may potentiate the activation of NLRC4 by flagellin.

Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3
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Tables

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Table 1

Human genetic diseases associated with polymorphisms in NLR genes

Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3
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Table 2

Triggers of NLR inflammasomes

Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3

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