MDP-NOD2 stimulation induces HNP-1 secretion, which contributes to NOD2 antibacterial function

Yamamoto-Furusho, Jesús K.; Barnich, Nicolas; Hisamatsu, Tadakazu; Podolsky, Daniel K.

doi:10.1002/ibd.21144

Cited by 32 publications

(31 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…NOD2-deficient mice display increased susceptibility to Staphylococcus aureus because of, in part, defective neutrophil phagocytosis, elevated serum levels of Th1 cytokines, and a higher bacterial tissue burden (11). However, stimulation of NOD2 with MDP was found to enhance host antibacterial function in vitro (12).…”

Section: Apoementioning

confidence: 99%

Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss

Yuan¹,

Zelkha²,

Burkatovskaya³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Significance Apolipoprotein E −/− (ApoE −/− ) mice deficient in nucleotide binding oligomerization domain-containing protein 2 (NOD2) and subjected to an oral gavage of Porphyromonas gingivalis developed elevated serum inflammatory cytokines, cholesterol, alveolar bone loss, and atherosclerosis. Stimulation of NOD2 by Muramyl DiPeptide (MDP) in ApoE −/− mice reduced P. gingivalis -induced inflammatory cytokines, cholesterol, alveolar bone loss, and atherosclerosis by reducing the expression of inhibitor of NF-κB kinase-β, NF-κB, JNK mRNA, and TNF-α protein levels. A reduction in body weight gain was observed in ApoE −/− mice fed a high-fat diet (HFD) and injected with MDP compared to ApoE −/− mice fed a HFD but saline injected. MDP activation of NOD2 should be considered in the treatment of inflammatory processes affecting atherosclerosis, bone loss, and possibly, weight gain.

show abstract

Section: Apoementioning

confidence: 99%

Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss

Yuan¹,

Zelkha²,

Burkatovskaya³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…MDP stimulation during Salmonella infection enhances bacterial clearance in a NOD2-dependent manner (12,13,35,51), and TRAF4 has been shown to inhibit NOD2-enhanced Salmonella killing by a mechanism dependent on a physical interaction of TRAF4 with NOD2 (34). We therefore tested whether TRAF4 phosphorylation was critical for inhibition of NOD2 antibacterial activity.…”

Section: Resultsmentioning

confidence: 99%

IκB Kinase α Phosphorylation of TRAF4 Downregulates Innate Immune Signaling

Marinis

Hutti

Homer

et al. 2012

Molecular and Cellular Biology

View full text Add to dashboard Cite

e Despite their homology, IB kinase ␣ (IKK␣) and IKK␤ have divergent roles in NF-B signaling. IKK␤ strongly activates NF-B while IKK␣ can downregulate NF-B under certain circumstances. Given this, identifying independent substrates for these kinases could help delineate their divergent roles. Peptide substrate array technology followed by bioinformatic screening identified TRAF4 as a substrate for IKK␣. Like IKK␣, TRAF4 is atypical within its family because it is the only TRAF family member to negatively regulate innate immune signaling. IKK␣'s phosphorylation of serine-426 on TRAF4 was required for this negative regulation. Binding to the Crohn's disease susceptibility protein, NOD2, is required for TRAF4 phosphorylation and subsequent inhibition of NOD2 signaling. Structurally, serine-426 resides within an exaggerated ␤-bulge in TRAF4 that is not present in the other TRAF proteins, and phosphorylation of this site provides a structural basis for the atypical function of TRAF4 and its atypical role in NOD2 signaling.

show abstract

“…NOD2-deficient mice have increased commensal bacteria and a decreased ability to prevent colonization of pathogenic bacteria (37). NOD2 has been reported as an antibacterial factor in epithelial cells and Paneth cells, whose antibacterial responses include defensin secretion (25,29,30,33). The role of TRAF4 in NOD2-induced bacterial killing was examined by observing the effect of TRAF4 on NOD2-induced Salmonella killing in gentamycin protection assays.…”

Section: Discussionmentioning

confidence: 99%

“…TRAF4 Binding to NOD2 Inhibits NOD2-induced Bacterial Killing-It has been shown that NOD2 plays an important role in the clearance of the intracellular bacterium, Salmonella typhimurium (25,29,30). In light of this, the role of TRAF4 in NOD2-induced bacterial killing was examined by studying the effect of TRAF4 on NOD2-induced Salmonella killing in gentamycin protection assays.…”

Section: Traf4 Inhibits Nod2-induced Nf-b Activation-nod2mentioning

confidence: 99%

“…In light of this, the role of TRAF4 in NOD2-induced bacterial killing was examined by studying the effect of TRAF4 on NOD2-induced Salmonella killing in gentamycin protection assays. HCT116 cells, a human epithelial colorectal carcinoma cell line that expresses endogenous NOD2 (30), were transfected with a vector control plasmid DNA, control shRNA, NOD2 shRNA, or TRAF4 FIGURE 3. TRAF4 inhibits RIP2 activation.…”

Section: Traf4 Inhibits Nod2-induced Nf-b Activation-nod2mentioning

confidence: 99%

See 1 more Smart Citation

A Novel Motif in the Crohn's Disease Susceptibility Protein, NOD2, Allows TRAF4 to Down-regulate Innate Immune Responses

Marinis

Homer

McDonald

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

The Crohn's disease and early onset sarcoidosis susceptibility protein, NOD2, coordinates innate immune signaling pathways. Because dysregulation of this coordination can lead to inflammatory disease, maintaining appropriate activation of the NOD2 signaling pathway is paramount in immunologic homeostasis. In this work, we identify the atypical tumor necrosis factor-associated factor (TRAF) family member, TRAF4, as a key negative regulator of NOD2 signaling. TRAF4 inhibits NOD2-induced NF-B activation and directly binds to NOD2 to inhibit NOD2-induced bacterial killing. We find that two consecutive glutamate residues in NOD2 are required for interaction with TRAF4 and inhibition of NOD2 signaling because mutation of these residues abrogated both TRAF4 binding and inhibition of NOD2. This work identifies a novel negative regulator of NOD2 signaling. Additionally, it defines a TRAF4 binding motif within NOD2 involved in termination of innate immune signaling responses.Upon intracellular exposure to bacterial products, the Crohn's disease susceptibility protein, NOD2 (nucleotidebinding oligomerization domain 2), initiates innate immune inflammatory signaling pathways to help tailor the adaptive immune system such that it can eradicate offending pathogens (1-3). Both the induction and the termination of NOD2 signaling are important to immune homeostasis and must be tightly controlled. Genetic variants of NOD2 result in dysregulated signaling and are associated with inflammatory disorders, including Crohn's disease, early onset sarcoidosis (EOS), 2 and Blau syndrome (4 -6). Although the signaling cascade linking NOD2 stimulation to NF-B activation has been extensively studied, the mechanisms by which NOD2, itself, is regulated remain elusive.Upon intracellular exposure to a breakdown product of bacterial peptidoglycan, muramyl dipeptide (MDP), NOD2 binds to the scaffolding protein kinase, RIP2 (receptor-interacting protein 2), via caspase recruitment domain interactions (1, 7). Following activation of the NOD2-RIP2 complex, the (CARD) IKK scaffolding protein IKK␥ (NEMO) becomes polyubiquitinated via Lys 63 linkages on Lys 285 of NEMO. These ubiquitin chains on NEMO are thought to help nucleate TAK1 (TNF receptor-associated kinase 1) such that it can phosphorylate the activation loop of IKK␤ and ultimately activate the NF-B transcription factors (8 -11).Previous work from this laboratory shows that one point of coordination for NOD2-induced innate immune signaling occurs at the level of the mitogen-activated protein kinase kinase kinases (MAP3Ks). MAP3Ks are the upper tier of a sequential cascade of MAPK-activating kinases that ultimately leads to MAPK activation. Specifically, the MAP3K, MEKK4, was identified as a regulator of NOD2. Both basally and in response to MDP, MEKK4 helps the cell to maintain low levels of NF-B activity (12). In addition to phosphorylating MAP2Ks, the MAP3K proteins act as scaffolding proteins for signaling complexes (13). This is evidenced by the fact that one atypical tumor necrosis recepto...

show abstract

MDP-NOD2 stimulation induces HNP-1 secretion, which contributes to NOD2 antibacterial function

Cited by 32 publications

References 41 publications

Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss

Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss

IκB Kinase α Phosphorylation of TRAF4 Downregulates Innate Immune Signaling

A Novel Motif in the Crohn's Disease Susceptibility Protein, NOD2, Allows TRAF4 to Down-regulate Innate Immune Responses

Contact Info

Product

Resources

About