Rip2 Participates in Bcl10 Signaling and T-cell Receptor-mediated NF-κB Activation

Ruefli-Brasse, Astrid; Lee, Wyne P.; Hurst, Stephen; Dixit, Vishva M.

doi:10.1074/jbc.c300460200

Cited by 88 publications

(87 citation statements)

References 24 publications

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“…Moreover, the pan-PKC inhibitor GFX did not affect the Ser 138 -dependent initial phosphorylation of Bcl10 nor the TCR-induced F-actin increase, but showed an inhibitory effect on a second, as yet unidentified site of Bcl10 phosphorylation that is thus unlikely to be relevant for actin polymerization. The receptor-interacting protein (RIP) family kinase RIP2 has been shown to associate with Bcl10 and to induce its phosphorylation upon TCR stimulation in the context of NF-B activation (15). Additional experiments are required to identify the RIP2-dependent phosphorylation site(s) in Bcl10 and to assess whether RIP2-mediated Bcl10 phosphorylation contributes to the effect on the actin cytoskeleton described here.…”

Section: Discussionmentioning

confidence: 99%

Bcl10 Controls TCR- and FcγR-Induced Actin Polymerization

Azagra

Gaide

Ho³

et al. 2007

The Journal of Immunology

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Bcl10 plays an essential role in the adaptive immune response, because Bcl10-deficient lymphocytes show impaired Ag receptor-induced NF-κB activation and cytokine production. Bcl10 is a phosphoprotein, but the physiological relevance of this posttranslational modification remains poorly defined. In this study, we report that Bcl10 is rapidly phosphorylated upon activation of human T cells by PMA/ionomycin- or anti-CD3 treatment, and identify Ser138 as a key residue necessary for Bcl10 phosphorylation. We also show that a phosphorylation-deficient Ser138/Ala mutant specifically inhibits TCR-induced actin polymerization yet does not affect NF-κB activation. Moreover, silencing of Bcl10, but not of caspase recruitment domain-containing MAGUK protein-1 (Carma1) induces a clear defect in TCR-induced F-actin formation, cell spreading, and conjugate formation. Remarkably, Bcl10 silencing also impairs FcγR-induced actin polymerization and phagocytosis in human monocytes. These results point to a key role of Bcl10 in F-actin-dependent immune responses of T cells and monocytes/macrophages.

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Section: Discussionmentioning

confidence: 99%

Bcl10 Controls TCR- and FcγR-Induced Actin Polymerization

Azagra

Gaide

Ho³

et al. 2007

The Journal of Immunology

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“…Interestingly, genetic evidence of a role for RIP2 has recently been reported in T-cell signaling (Ruefli-Brasse et al, 2004). RIP2 associates with BCL10 and is necessary for TCR-induced BCL10 phosphorylation and IKK activation.…”

Section: Role Of Nf-jb In the Adaptive Responsementioning

confidence: 99%

NF-κB and the immune response

2006

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“…The two initial reports on Rip2 À/À mice mentioned above suggested that these mice had intrinsic defective Th1 immune responses and that Rip2 was required for optimal activation of NF-kB and T-cell proliferation upon TCR stimulation [6,27]. Rip2 was shown to associate with Bcl10, a signaling molecule of the TCR-induced NF-kB pathway, after T-cell stimulation [30]. The same group also reported a delayed allograft rejection of neonatal heart tissue in Rip2-deficient mice, suggesting impaired adaptive immunity in the absence of Rip2 [30].…”

Section: Introductionmentioning

confidence: 99%

“…Rip2 was shown to associate with Bcl10, a signaling molecule of the TCR-induced NF-kB pathway, after T-cell stimulation [30]. The same group also reported a delayed allograft rejection of neonatal heart tissue in Rip2-deficient mice, suggesting impaired adaptive immunity in the absence of Rip2 [30]. More recently, using fully backcrossed animals, other reports failed to identify intrinsic defects of the adaptive immune system in Rip2-deficient mice [31,32].…”

Section: Introductionmentioning

confidence: 99%

Essential role of Rip2 in the modulation of innate and adaptive immunity triggered by Nod1 and Nod2 ligands

Magalhães¹,

Lee²,

Geddes³

et al. 2011

Eur J Immunol

110

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Muramyl peptides are the building blocks of bacterial peptidoglycan, and their biological functions in mammals have been extensively studied. In particular, muramyl peptides trigger inflammation, contribute to host defense against microbial infections, and modulate the adaptive immune response to antigens. These bacterial molecules are detected by nucleotide oligomerization domain 1 (Nod1) and Nod2, and recent evidence suggests that muramyl dipeptide also activates NLRP3 and NLRP1 inflammasomes. Here, we investigated the role of Rip2, the adaptor for Nod1-and Nod2-dependent signaling, in multiple aspects of the host response to muramyl peptides in vivo, such as inflammatory cytokine secretion, activation and recruitment of macrophages and neutrophils to the site of injection, systemic activation of myeloid, T and B cells in the spleen, adjuvanticity and capacity to polarize the adaptive response to ovalbumin. Our results demonstrate that Rip2 was crucial for all the biological functions studied. We also identified CD11c int CD11b 1 inflammatory dendritic cells as a major myeloid cell population responding to Nod stimulation in vivo. Together, our results highlight the importance of Rip2 for Nod-dependent induction of innate and adaptive immunity.Keywords: CD11c int CD11b 1 inflammatory DC . Nod 1/2 . Rip2Supporting Information available online IntroductionThe innate immune system plays a crucial role in host defense against invading pathogens, and relies on pattern recognition molecules (PRMs), which detect conserved microbial-and danger-associated molecular patterns (MAMPs or DAMPs). The best-studied PRMs are the Toll-like receptors (TLRs), which localize either at the cell surface or within endosomes. More recently, intracellular cytosolic PRMs, such as the nucleotide oligomerization domain (Nod)-like receptors (NLRs) and the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), have been identified. Nod1 and Nod2 are NLR proteins that trigger nuclear factorkB (NF-kB) signaling in response to bacterial peptidoglycan. Specifically, Nod1 recognizes muramyl peptides containing meso-DAP (diaminopimelic acid) found in the peptidoglycan of most Gram-negative bacteria and certain Gram-positive bacteria [1,2], whereas Nod2 recognizes muramyl dipeptide (MDP) produced in all bacteria [3,4]. Upon peptidoglycan detection, Nod1 and Nod2 recruit and associate with the adaptor protein Ã These authors have contributed equally to this study. [11,12]. Moreover, Nod1 and Nod2 induce the production of nitric oxide, a molecule that is known to be directly microbicidal [13][14][15]. Activation of Nod1 and Nod2 by live bacteria triggers proinflammatory responses, leading to the induction of cytokine and chemokines [16,17]. Using Nod-deficient mice, several in vivo studies have demonstrated a key role for Nod1 and Nod2 in host defense against pathogens such as H. pylori, L. monocytogenes, and Staphylococcus aureus [12,18,19].In addition to contributing to innate immunity, Nod1 and Nod2 have been implicated in the induction o...

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Rip2 Participates in Bcl10 Signaling and T-cell Receptor-mediated NF-κB Activation

Abstract: Engagement of the T-cell receptor (TCR) initiates

Cited by 88 publications

References 24 publications

Bcl10 Controls TCR- and FcγR-Induced Actin Polymerization

Bcl10 Controls TCR- and FcγR-Induced Actin Polymerization

NF-κB and the immune response

Essential role of Rip2 in the modulation of innate and adaptive immunity triggered by Nod1 and Nod2 ligands

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