https://padlet.com/irish_vet/iwnbk9or3mcz Human gastrointestinal tract en-us 2018-01-25 17:14:28 UTC 2025-03-01 10:02:49 UTC hello@padlet.com irish_vet https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224762351 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.

]]> 2018-01-25 17:16:42 UTC https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224762351 irish_vet https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224767667 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]]> 2018-01-25 17:25:45 UTC https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224767667 irish_vet https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224771403

NODs are expressed by:

• Epithelial cells
• Stromal cells
• Neutrophils
• Dendritic cells
• Paneth cells

]]> 2018-01-25 17:32:42 UTC https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224771403 irish_vet https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224772429

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

]]> 2018-01-25 17:34:36 UTC https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224772429 irish_vet https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224774201 2018-01-25 17:38:08 UTC https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224774201 irish_vet https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224775647

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

]]> 2018-01-25 17:40:30 UTC https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224775647 irish_vet https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224777456

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

]]> 2018-01-25 17:43:47 UTC https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224777456 irish_vet https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224779215 2018-01-25 17:47:19 UTC https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224779215 irish_vet https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224779855

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

]]> 2018-01-25 17:48:37 UTC https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224779855 irish_vet https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224782946 2018-01-25 17:53:43 UTC https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224782946 irish_vet https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224783827

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

]]> 2018-01-25 17:55:11 UTC https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224783827 irish_vet https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224785528 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     ]]> 2018-01-25 17:57:55 UTC https://padlet.com/irish_vet/iwnbk9or3mcz/wish/224785528