# data[].attributes.body
NOD = Nucleotide-binding oligomerisation domain-containing protein

NOD1 and NOD2

Cytosolic proteins

Respond to intracellular fragments of bacterial peptidoglycans → initiate nuclear factor-κB dependent and mitogen-activated protein kinase dependent gene transcription

NOD 1 detects d-glutamyl-meso-diaminopimelic acid which is a:

Dipeptide present in a peptidoglycan

Primarily found in Gram-negative bacteria but also in select groups of Gram-positive bacteria, including Listeria spp. and Bacillus spp.

# data[].attributes.body
NOD1 (nucleotide-binding oligomerization domain-containing protein 1) contains a single amino-terminal caspase recruitment domain (CARD), and NOD2 contains tandem N-terminal CARDs that interact with the CARD of receptor-interacting protein 2 (RIP2). Both NOD1 and NOD2 contain a central nucleotide-binding domain (NBD), which binds ATP and mediates NOD oligomerization, and carboxy-terminal leucine-rich repeats (LRRs), which are important for ligand sensing

# data[].attributes.body
NODs are expressed by:

Epithelial cells

Stromal cells

Neutrophils

Dendritic cells

Paneth cells

# data[].attributes.body
NLRP proteins interact with pyrin-containing proteins

Form inflammasomes

Cleave pro-IL-1β and pro-IL-18 into there mature forms by using the caspase-1 pathway

Activation of caspace pathway → pyroptosis

NLRP’s recognise both bacterial products (e.g. flagellin, toxins) and crystals (e.g. urea)

NOD signalling in the stromal compartments is required for the formation of intestinal lymphoid follicles

Interactions between NODs and the microbiome are also essential

NODs are also required for appropriate microfloral control
NOD2 deficiency increases bacterial load and decreases the clearance of bacteria from the intestinal crypts

# data[].attributes.body
Nucleotide binding function

NBD’s of NOD1 and NOD2 mediate ligand induced oligomerisation and hydrolyse ATP

ATP binding is required for NOD1 and NOD2 activation

ATP hydrolysis is required for NOD2 deactivation

Activation and regulation of RIP2

Sensing their perspective peptidoglycan ligands

NOD1 and NOD 2 auto- oligomerisation

Activation of RIP2

Recruitment and activation of TAK1-TAB2-TAB3 complex

Drives IKK complex activation

1κBα phosphorylation and degradation

# data[].attributes.body
Activation of MAPKs extracellular signal regulated kinase 1 (ERK1), ERK2, JUNN – Terminal kinase (JNK)and p38

Leads to expression of pro-inflammatory immune factors

TNF

IL6

CC-chemokine ligand 2 (CCL)

Neutrophil chemoattractants

CXC-chemokine ligand 8 (CXCL8)

CXCL2

Various antimicrobial factors including defensins

Recruitment and priming of innate immune cells

Primes adaptive immune system

Key driver of TH2-type immunity

Activation of IFN regulatory factor 7 (IFN 7)

Transcription of type 1 IFN genes

Activation of the IFN-stimulated gene factor 3 (ISGF3) complex

Initiate transcriptional programme associated with viral infection

# data[].attributes.body
NOD 2 has an important role in intestinal homeostasis by:

Detecting peptidoglycan released from the gut microbiota

Driving the physiological inflammatory programme through the kinase RIP2 leading to NF-κB activation

In Crohn’s disease

Associated with NOD2 mutations

Some perturbation which may include antibiotics or an infection alters the protective inflammatory programme

Breakdown of intestinal barrier

Compensatory immune activation pathways then drives chronic inflammation

# data[].attributes.headline
NOD signalling and intestinal barrier - Homeostasis and Crohn's disease

# data[].attributes.subject
NOD signalling and intestinal barrier - Homeostasis and Crohn's disease

# data[].attributes.body
Loss of function mutations of NOD2

Affecting NOD2-mediated peptidoglycan sensing

Associated with Crohn’s disease

Gain of function mutations in the NBD of NOD 2 correlate with

Autoimmune disease

Blau syndrome

Early onset sarcoidosis

# data[].attributes.body
Philpott, D., Sorbara, M., Robertson, S., Croitoru, K., Girardin, S. 2014. NOD proteins: regulators of inflammation in health and disease. Nature Reviews Immunology 14, 9–23