NOD-like Receptor Signaling Pathways

Click on one of the NOD-like receptors below to see a select list of the pathogen- or damage-associated molecules recognized by each receptor and the intracellular signaling pathways that are activated as a result.

Bacterial Type III or IV
Secretion Systems
Bacterial Type III or IV
Secretion Systems
Phagosome
or Endosome
Phagosome
or Endosome
Bacterial
PGN Components
Bacterial
PGN Components
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NOD1
NOD1
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cIAP-1 or
cIAP-2
cIAP-1 or
cIAP-2
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RIP2/RICK
RIP2/RICK
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NOD2
NOD2
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cIAP-1 or
cIAP-2
cIAP-1 or
cIAP-2
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CARD9
CARD9
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RIP2/RICK
RIP2/RICK
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TAB1/2/3
TAB1/2/3
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TAK1
TAK1
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IKK
IKK
I kappa B
I kappa B
I kappa B
I kappa B
Proteasome
Proteasome
NF-kappa B
NF-kappa B
NF-kappa B
NF-kappa B
MKK
MKK
ERK1/2
ERK1/2
p38
p38
JNK
JNK
AP-1
AP-1
Pro-inflammatory Cytokines:
Pro-inflammatory Cytokines:
IL-1 beta
IL-1 beta
IL-6
IL-6
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IL-8
IL-8
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TNF-alpha
TNF-alpha
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IL-18
IL-18
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IRF3
or IRF7
IRF3
or IRF7
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IRF3 or IRF7
Homodimer
IRF3 or IRF7
Homodimer
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IRF3 or IRF7
IRF3 or IRF7
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Type I IFN &
IFN-inducible genes
Type I IFN &
IFN-inducible genes
Toll-like
Receptor
Toll-like
Receptor
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NLRC3 or NLRX1
NLRC3 or NLRX1
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P2X7 Receptor
P2X7 Receptor
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ATP
ATP
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Pannexin-1
Pannexin-1
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ROS
ROS
K+ Channel
K+ Channel
K+ Efflux
K+ Efflux
K+
K+
Bacterial Type III or IV
Secretion Systems
Bacterial Type III or IV
Secretion Systems
Particulate
Activators
Particulate
Activators
Ca2+ Channel
Ca2+ Channel
Ca2+
Ca2+
Ca2+ Influx
Ca2+ Influx
Phagosome
Phagosome
Phagolysosome
Phagolysosome
Membrane Perturbations
Membrane Perturbations
ROS
ROS
Transcription of Pro-IL-1 beta
and Pro-IL-18
Transcription of Pro-IL-1 beta
and Pro-IL-18
Inflammasome Activation
Inflammasome Activation
Inflammasome
Oligomerization
Inflammasome
Oligomerization
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NLRP1/NALP1
NLRP1/NALP1
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NLRP3/NALP3
NLRP3/NALP3
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NLRC4/IPAF
NLRC4/IPAF
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NLRP7/NALP7
NLRP7/NALP7
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or
or
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NLRP12/NALP12
NLRP12/NALP12
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Pro-Caspase-5
Pro-Caspase-5
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NLRP1/
NALP1
NLRP1/
NALP1
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ASC
ASC
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Pro-Caspase-1
Pro-Caspase-1
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NLRP3/
NALP3
NLRP3/
NALP3
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ASC
ASC
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Cardinal
Cardinal
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Pro-Caspase-1
Pro-Caspase-1
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NAIP
NAIP
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ASC
ASC
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NLRC4/
IPAF
NLRC4/
IPAF
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Pro-Caspase-1
Pro-Caspase-1
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or
or
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NLRC4/
IPAF
NLRC4/
IPAF
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ASC
ASC
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Pro-Caspase-1
Pro-Caspase-1
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NLRP7
NLRP7
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or
or
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NLRP12
NLRP12
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ASC
ASC
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Pro-Caspase-1
Pro-Caspase-1
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Active Caspase-1
Active Caspase-1
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Pyroptosis
Pyroptosis
Pro-IL-1 beta
Pro-IL-1 beta
Pro-IL-18
Pro-IL-18
Mature IL-1 beta
Mature IL-1 beta
Mature IL-18
Mature IL-18
Inflammatory Response
Inflammatory Response
NOD1
Select Agonist(s)
Meso-diaminopimelic acid
NOD2
Select Agonist(s)
Muramyl dipeptide
NLRP1/NALP1
Select Agonist(s)
Bacillus anthracis lethal toxin
Muramyl dipeptide
NLRP3/NALP3
Select Agonist(s)
Adenoviral DNA
Bacterial RNA
Influenza and Sendai virus RNA
Lipopolysaccharide
Pore-forming toxins: Hemolysins, Nigericin,
Pneumolysin
Exogenous compounds: Silica, Asbestos, Alum
Danger signals: Extracellular ATP, extracellular NAD+,
beta-amyloid and particulates such as calcium pyrophosphate dihydrate and monosodium urate
Candida albicans
Saccharomyces cerevisiae
Klebsiella pneumoniae
Mycobacterium tuberculosis
Salmonella typhimurium
Schistosoma mansoni
NLRP7/NALP7
Select Agonist(s)
Acylated microbial lipopeptides
NLRP12/NALP12
Select Agonist(s)
Yersinia pestis
NLRC4/IPAF
Select Agonist(s)
Legionella pneumophila
Pseudomonas aeruginosa
Salmonella typhimurium
Shigella flexneri
NAIP
Select Agonist(s)
Flagellin (Naip5)
Components of the bacterial type III secretion apparatus (Naip2)

Overview of NOD-like Receptors

Nucleotide-binding, oligomerization domain (NOD)-like receptors (NLRs) are a family of cytosolic proteins that play an important role in inflammation and immunity. The NLR family consists of twenty-two human proteins and at least thirty-four mouse proteins that contain a central nucleotide-binding, oligomerization domain (NOD or NACHT), a variable number of C-terminal leucine-rich repeats, and an N-terminal protein interaction domain. Similar to the leucine-rich repeat-containing toll-like receptors (TLRs), multiple NLRs function as pattern recognition receptors. These NLRs are responsible for detecting specific pathogen-associated molecules or host-derived damage signals in the cytosol and initiating the innate immune response. NOD1/NLRC1 and NOD2/NLRC2 are two pattern recognition receptors that are activated by specific components of bacterial peptidoglycan. Their activation triggers signaling pathways that drive the NF-kappa B-/AP-1-dependent expression of pro-inflammatory cytokines and the IRF3- and/or IRF7-dependent expression of type I interferons. Additionally, activation of NOD1 and NOD2 can induce autophagy through an interaction with Autophagy-related 16-like 1 (ATG16L1). Although a clear connection between NOD1 and chronic inflammatory diseases has not been well-established, mutations in NOD2 have been linked to Crohn’s disease and Blau syndrome.

Other NLRs that function as pattern recognition receptors, including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4/IPAF, and NAIP, oligomerize to form multiprotein inflammasome complexes following their activation by different pathogens or endogenous danger signals. Inflammasome oligomerization leads to the cleavage and activation of Caspase-1, which subsequently promotes the processing and secretion of IL-1 beta and IL-18, and can induce an inflammatory form of cell death known as pyroptosis. The NLRP1, NLRP3, and NLRC4/IPAF inflammasomes are the most fully characterized NLR-containing inflammasomes. They consist of a specific NLR protein, Apoptosis-associated Speck-like protein containing a CARD (ASC), Pro-Caspase-1, and inflammasome-specific proteins such as the Cardinal adaptor protein (NLRP3), Pro-Caspase-5 (NLRP1), or NAIP (NLRC4/IPAF). Inflammasome-mediated secretion of IL-1 beta and IL-18 is aimed at eliminating the infectious pathogen through the induction of secondary mediators and the recruitment of additional immune cells to the infection site and/or pyroptosis of the infected cells. While the inflammasome-mediated response is beneficial for the host, it must be tightly regulated as mutations that result in constitutive inflammasome activation have been linked to autoinflammatory disorders such as Familial Cold Auto-inflammatory Syndrome (FCAS), Familial Mediterranean Fever (FMF), Muckle-Wells Syndrome (MWS), and Chronic Infantile Neurologic Cutaneous and Articular Syndrome (CINCA). In addition, a number of other diseases such as inflammatory bowel disease, type 1 and type 2 diabetes, vitiligo, gout, and multiple sclerosis have also been suggested to be associated with inappropriate or chronic inflammasome activation.

In contrast to the NLRs involved in pathogen recognition, other members of the NLR family have been suggested to have anti-inflammatory effects due to their abilities to either negatively regulate NF-kappa B signaling or inhibit Caspase-1-mediated IL-1 beta secretion. Although these proteins have not been as widely investigated, preliminary studies suggest that NLRC3, NLRP2, NLRP4, NLRP7, NLRP10/PYNOD, NLRP12, and NLRX1 may have anti-inflammatory properties. In addition, there are two other unique NLRs, NLRC5 and Class II transactivator (CTIIA), that function as transcriptional regulators of MHC class I and MHC class II gene expression, respectively. Besides these activities, some NLR proteins may have additional immune modulatory functions. For example, NLRP10/PYNOD and NLRP12 have been shown to be involved in mediating dendritic cell migration and initiation of the adaptive immune response. Further research is necessary to determine whether other proteins belonging to the NLR family also have unique cell type-specific or context-dependent functions that play a role in regulating the immune response.

To learn more, please visit our NOD-like Receptors and the Inflammasome Research Area.

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