NOD1 and NOD2 receptors: integral members of the innate and adaptive immunity system.

Antosz, H; Osiak, Magdalena

doi:10.18388/abp.2013_1992

Cited by 14 publications

(6 citation statements)

References 117 publications

(108 reference statements)

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“…The present study identified CYLD as a novel and important inhibitor of RIPK2-dependent protective immune responses in Lm-infected murine macrophages. Activation of RIPK2 by the Lm-sensing intracellular pattern-recognition receptor NOD2 is essential for the downstream stimulation of the NF-κB and MAPK pathways ( 42 , 43 ), NOD2-induced immune responses in macrophages ( 25 ) and the control of listeriosis in vivo ( 17 ). Previous studies have shown that CYLD limited RIPK2-mediated activation of NF-κB by removing K63-polyubiquitin chains from NEMO ( 8 , 44 ).…”

Section: Discussionmentioning

confidence: 99%

Receptor-Interacting Protein Kinase-2 Inhibition by CYLD Impairs Antibacterial Immune Responses in Macrophages

et al. 2016

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Upon infection with intracellular bacteria, nucleotide oligomerization domain protein 2 recognizes bacterial muramyl dipeptide and binds, subsequently, to receptor-interacting serine/threonine kinase 2 (RIPK2), which activates immune responses via the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) and extracellular signal-regulated kinase (ERK) pathways. Activation of RIPK2 depends on its K63 ubiquitination by E3 ligases, whereas the deubiquitinating enzyme A20 counter regulates RIPK2 activity by cleaving K63-polyubiquitin chains from RIPK2. Here, we newly identify the deubiquitinating enzyme CYLD as a new inhibitor of RIPK2. We show that CYLD binds to and removes K63-polyubiquitin chains from RIPK2 in Listeria monocytogenes (Lm) infected murine bone marrow-derived macrophages. CYLD-mediated K63 deubiquitination of RIPK2 resulted in an impaired activation of both NF-κB and ERK1/2 pathways, reduced production of proinflammatory cytokines interleukin-6 (IL-6), IL-12, anti-listerial reactive oxygen species (ROS) and nitric oxide (NO), and, finally, impaired pathogen control. In turn, RIPK2 inhibition by siRNA prevented activation of NF-κB and ERK1/2 and completely abolished the protective effect of CYLD deficiency with respect to the production of IL-6, NO, ROS, and pathogen control. Noteworthy, CYLD also inhibited autophagy of Listeria in a RIPK2-ERK1/2-dependent manner. The protective function of CYLD deficiency was dependent on interferon gamma (IFN-γ) prestimulation of infected macrophages. Interestingly, the reduced NF-κB activation in CYLD-expressing macrophages limited the protective effect of IFN-γ by reducing NF-κB-dependent signal transducers and activators of transcription-1 (STAT1) activation. Taken together, our study identifies CYLD as an important inhibitor of RIPK2-dependent antibacterial immune responses in macrophages.

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Section: Discussionmentioning

confidence: 99%

Receptor-Interacting Protein Kinase-2 Inhibition by CYLD Impairs Antibacterial Immune Responses in Macrophages

et al. 2016

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“…The mechanism through which ingested parasites may come into contact with NOD1 and NOD2, thereby triggering the synthesis of a variety of different cytokines, is poorly understood and still a matter of debate. On the basis of their cytosolic localization, NODs may respond to intracytosolic bacteria that have evaded from the phagosome, bacterial components delivered to the cytosol via the secretion systems or through created pores, and bacterial products delivered by phagocytosis or pinocytosis [29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

NOD1 and NOD2 Interact with the Phagosome Cargo in Mast Cells: A Detailed Morphological Evidence

et al. 2014

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Mast cells (MC) play a key role in triggering the inflammatory process and share some functions with professional phagocytes. It is not clear whether or not the phagocytic process in MC follows the same route and has the same meaning of that of professional phagocytes. Herein we analyze in detail the structure of the phagosome in rat peritoneal mast cells (RPMC). The ultrastructural analysis of the phagosome, containing either model particles or bacteria, reveals that these vacuoles are very tight, and in several areas, their membrane seems to have dissolved. RPMC express NOD1 and NOD2 proteins whose role is to recognize intracellular foreign components and induce the production of pro-inflammatory mediators. Following Escherichia coli ingestion, both these molecules are found on the phagosome membrane and on ingested pathogens, together with phagosome maturation markers. These findings suggest that in RPMC the ingested cargo can, through interruptions of the phagosome membrane, interact directly with NODs, which act as switches in the process of cytokine production.

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“…31 The mutations have been shown to lead to significant hyperactivity of NOD1 and NOD2 receptors after ligand stimulation. 32 Therefore, we suggest that the NOD1 rs2075818 polymorphism may contribute to the pathogenesis of subacute sclerosing panencephalitis. There have been no studies yet on the NOD1 gene polymorphisms in subacute sclerosing panencephalitis.…”

Section: Discussionmentioning

confidence: 85%

Association of NOD1 and NOD2 Polymorphisms With Susceptibility to Subacute Sclerosing Panencephalitis

et al. 2022

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Background: Subacute sclerosing panencephalitis is a progressive neurodegenerative disease that is a late complication of measles infection. However, to date, the pathogenesis of subacute sclerosing panencephalitis is still not explained; both viral and host factors seem to be associated. The present study aimed to investigate the relationship between NOD1 and NOD2 gene variants and subacute sclerosing panencephalitis. Methods: The gene variants of NOD1 (rs2075820 and rs2075818) and NOD2 (R334Q and R334W) were explored in 64 subacute sclerosing panencephalitis patients and 70 controls using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Results: The frequencies of the AA genotype and A allele of rs2075820 ( NOD1; c.796G>A) polymorphism were lower in patients compared with controls ( P = .022 and .014, respectively). The presence of the A allele of rs2075820 may be considered as a protective factor for subacute sclerosing panencephalitis. There was a significant difference between the groups in rs2075818 ( NOD1 G/C) polymorphism, and the CC genotype increased the risk of subacute sclerosing panencephalitis by 3.471-fold. The carriers of the C allele of rs2075818 (G/C) had a 1.855-fold susceptibility to subacute sclerosing panencephalitis ( P = .018). The GC genotype might be associated with subacute sclerosing panencephalitis susceptibility in the patients compared with patients without having that haplotype ( P = .03). Conclusions: Thus, we identified an association between subacute sclerosing panencephalitis and the rs2075820 ( NOD1 G/A) and rs2075818 ( NOD1 G/C) polymorphisms. These findings implicate a possible effect of this genetic polymorphism in susceptibility to subacute sclerosing panencephalitis, which needs to be confirmed in bigger populations.

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NOD1 and NOD2 receptors: integral members of the innate and adaptive immunity system.

Cited by 14 publications

References 117 publications

Receptor-Interacting Protein Kinase-2 Inhibition by CYLD Impairs Antibacterial Immune Responses in Macrophages

Receptor-Interacting Protein Kinase-2 Inhibition by CYLD Impairs Antibacterial Immune Responses in Macrophages

NOD1 and NOD2 Interact with the Phagosome Cargo in Mast Cells: A Detailed Morphological Evidence

Association of NOD1 and NOD2 Polymorphisms With Susceptibility to Subacute Sclerosing Panencephalitis

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