Nucleotide-binding Oligomerization Domain-1 and Epidermal Growth Factor Receptor

Boughan, Parjeet K.; Argent, Richard H.; Body-Malapel, Mathilde; Park, Jong‐Hwan; Ewings, Katie E.; Bowie, Andrew; Ong, Shao Jin; Cook, Simon J.; Sørensen, Ole E.; Manzo, Barbara A.; Inohara, Naohiro; Klein, Nigel; Núñez, Gabriel; Atherton, John C.; Bajaj-Elliott, Mona

doi:10.1074/jbc.m510275200

Cited by 157 publications

(41 citation statements)

References 69 publications

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“…In addition, transactivation of EGF receptor during human skin wound healing stimulates hBD-3 expression in skin keratinocytes (Sorensen et al, 2006). While signaling pathways that regulate expression of hBD-1 still remain unknown, hBD-2 is induced by pro-inflammatory mediators or bacterial products via activation of NF-κB transcription factors and STATs (Boughan et al, 2006; Chung and Dale, 2008). Kawsar et al (2010) have shown the expression of hBD-2 in microvasculature in the “keratin pearl” region of terminally differentiated OSCC.…”

Section: β-Defensins In Cancermentioning

confidence: 99%

The Yin and Yang of Human Beta-Defensins in Health and Disease

et al. 2012

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Rapidly evolving research examining the extended role of human beta-defensins (hBDs) in chemoattraction, innate immune-mediated response, and promotion of angiogenesis suggest that the collective effects of hBDs extend well beyond their antimicrobial mechanism(s). Indeed, the numerous basic cellular functions associated with hBDs demonstrate that these peptides have dual impact on health, as they may be advantageous under certain conditions, but potentially detrimental in others. The consequences of these functions are reflected in the overexpression of hBDs in diseases, such as psoriasis, and recently the association of hBDs with pro-tumoral signaling. The mechanisms regulating hBD response in health and disease are still being elucidated. Clearly the spectrum of function now attributed to hBD regulation identifies these molecules as important cellular regulators, whose appropriate expression is critical for proper immune surveillance; i.e., expression of hBDs in proximity to areas of cellular dysregulation may inadvertently exacerbate disease progression. Understanding the mechanism(s) that regulate contextual signaling of hBDs is an important area of concentration in our laboratories. Using a combination of immunologic, biochemical, and molecular biologic approaches, we have identified signaling pathways associated with hBD promotion of immune homeostasis and have begun to dissect the inappropriate role that beta-defensins may assume in disease.

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Section: β-Defensins In Cancermentioning

confidence: 99%

The Yin and Yang of Human Beta-Defensins in Health and Disease

et al. 2012

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“…NOD1 sensing of H. pylori peptidoglycan induces NF-κB activation and expression of type I IFN via IFN-Regulatory-Factor 7, MIP-2, and β-defensin (14,15,20,22) and H. pylori colonizes Nod1 −/− deficient mice more densely compared to wild-type mice (14,22). In humans, genetic variation in ATG16L1 , which encodes a key effector of NOD1-dependent autophagy and inflammation, alters susceptibility to H. pylori infection (25).…”

Section: Introductionmentioning

confidence: 99%

Modification of Helicobacter pylori Peptidoglycan Enhances NOD1 Activation and Promotes Cancer of the Stomach

et al. 2015

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Helicobacter pylori is the strongest known risk factor for gastric carcinogenesis. One cancer-linked locus is the cag pathogenicity island, which translocates components of peptidoglycan (PGN) into host cells. NOD1 is an intracellular immune receptor that senses PGN from Gram-negative bacteria and responds by inducing autophagy and activating NF-κB, leading to inflammation-mediated bacterial clearance; however chronic pathogens can evade NOD1-mediated clearance by altering PGN structure. We previously demonstrated that the H. pylori cag+ strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. Using 2D-DIGE and mass spectrometry, we identified a novel mutation within the gene encoding the peptidoglycan deacetylase PgdA; therefore, we sought to define the role of H. pylori PgdA in NOD1-dependent activation of NF-κB, inflammation, and cancer. Co-culture of H. pylori strain 7.13 or its pgdA− isogenic mutant with AGS gastric epithelial cells or HEK293 epithelial cells expressing a NF-κB reporter revealed that pgdA inactivation significantly decreased NOD1-dependent NF-κB activation and autophagy. Infection of Mongolian gerbils with an H. pylori pgdA− mutant strain led to significantly decreased levels of inflammation and malignant lesions in the stomach; however, pre-activation of NOD1 prior to bacterial challenge reciprocally suppressed inflammation and cancer in response to wild-type H. pylori. Expression of NOD1 differs in human gastric cancer specimens compared to non-cancer samples harvested from the same patients. These results indicate that PGN deacetylation plays an important role in modulating host inflammatory responses to H. pylori, allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche.

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“…Although Nod2 recognizes the muramyl dipeptide (MDP) structure in bacterial peptidoglycan (PGN)-related molecules, Nod1 senses the essential iE-DAP dipeptide, which is uniquely found in PGN of all Gram-negative and certain Gram-positive bacteria (8 -12). Previous studies suggested the involvement of Nod1 in the recognition of numerous bacteria including Helicobacter pylori (13,14), Listeria monocytogenes (15, 16), Shigella flexneri (17), several Bacillus species (18), and Propionibacterium acnes (7). Although the iE-DAP structure is found in the insoluble fraction of intact PGN, intermediates of PGN synthesis and cleaved PGN products produced during bacterial growth and PGN recycling (11,19), the identity of the major Nod1 stimulatory molecule (s) remains unknown (18).…”

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confidence: 99%

A Role of Lipophilic Peptidoglycan-related Molecules in Induction of Nod1-mediated Immune Responses

Hasegawa

Kawasaki

Yang

et al. 2007

Journal of Biological Chemistry

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Nod1 is an intracellular protein that is involved in recognition of bacterial molecules and whose genetic variation has been linked to several inflammatory diseases. Previous studies suggested that the recognition core of Nod1 stimulatory molecules is ␥-D-glutamyl-meso-diaminopimelic acid (iE-DAP), but the identity of the major Nod1 stimulatory molecule produced by bacteria remains unknown. Here we show that bacteria produce lipophilic molecules capable of stimulating Nod1. Analysis of synthetic compounds revealed stereoselectivity of the DAP residue and that conjugation of lipophilic acyl residues specifically enhances the Nod1 stimulatory activity of the core iE-DAP. Furthermore, we demonstrate that lipophilic molecules induce and/or enhance the secretion of innate immune mediators from primary mouse mesothelial cells and human monocytic MonoMac6 cells, and this effect is mediated through Nod1. These results provide insight into the mechanism of immune recognition via Nod1, which might be useful in the design and testing of novel immunoregulators.The innate immune receptors recognize specific molecules that are commonly found in microbes and induce host defense responses to eliminate invading pathogens (1). These pathogen-recognizing receptors include membrane-bound Toll-like receptors (TLRs) 2 as well as cytosolic Nod-like receptors and RIG-I family proteins. These three classes of pathogen-recognizing receptors regulate innate and acquired immune responses by inducing intracellular signaling pathways that lead to the activation of p38, c-Jun NH 2 -terminal kinase (JNK), extracellular signal-regulated kinases (ERKs), caspase-1, and transcription factors including NF-B and/or IRFs (1).Nod1 is the founding member of the Nod-like receptor protein family that contains nucleotide oligomerization domain (NOD) and ligand-recognizing leucine-rich repeats. This family is comprised of more than 20 members including Nod2, cryopyrin, Ipaf, NAIP, and NALP1 (1, 2). Genetic studies have revealed that variations of the NOD1 gene are associated with susceptibility to several human disorders including allergic diseases (3-5), Crohn disease (6), and sarcoidosis (7), although the mechanism underlying these disease associations remains poorly understood. Although Nod2 recognizes the muramyl dipeptide (MDP) structure in bacterial peptidoglycan (PGN)-related molecules, Nod1 senses the essential iE-DAP dipeptide, which is uniquely found in PGN of all Gram-negative and certain Gram-positive bacteria (8 -12). Previous studies suggested the involvement of Nod1 in the recognition of numerous bacteria including Helicobacter pylori (13,14), Listeria monocytogenes (15, 16), Shigella flexneri (17), several Bacillus species (18), and Propionibacterium acnes (7). Although the iE-DAP structure is found in the insoluble fraction of intact PGN, intermediates of PGN synthesis and cleaved PGN products produced during bacterial growth and PGN recycling (11,19), the identity of the major Nod1 stimulatory molecule (s) remains unknown (18). Previous s...

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Nucleotide-binding Oligomerization Domain-1 and Epidermal Growth Factor Receptor

Cited by 157 publications

References 69 publications

The Yin and Yang of Human Beta-Defensins in Health and Disease

The Yin and Yang of Human Beta-Defensins in Health and Disease

Modification of Helicobacter pylori Peptidoglycan Enhances NOD1 Activation and Promotes Cancer of the Stomach

A Role of Lipophilic Peptidoglycan-related Molecules in Induction of Nod1-mediated Immune Responses

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