The Inositol Phosphatase SHIP-1 Inhibits NOD2-Induced NF-κB Activation by Disturbing the Interaction of XIAP with RIP2

Condé, Claude; Rambout, Xavier; Lebrun, Marielle; Lecat, Aurore; Valentin, Emmanuel Di; Dequiedt, Samuel; Piette, Jacques; Gloire, Geoffrey; Legrand, Sylvie

doi:10.1371/journal.pone.0041005

Cited by 31 publications

(32 citation statements)

References 54 publications

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“…These are: NFKBIZ , which encodes IkBζ, a repressor of NF-κB signaling activator upstream of IL6 production and Th17 differentiation; 27, 28 INPP5D , which encodes a negative regulator of NF-κB signaling and IL12 production in macrophages; 29, 30, 31 and TEC , which encodes a protein tyrosine kinase required for lipopolysaccharide-induced expression of tumor necrosis factor (TNF)-α, IL1β and IL6. 14, 32 …”

Section: Resultsmentioning

confidence: 99%

GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis

Hussman¹,

Beecham

Schmidt

et al. 2016

Genes Immun

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Objective To identify genes and biologically relevant pathways associated with risk to develop multiple sclerosis (MS). Methods The Genome-Wide Association Studies noise-reduction method (GWAS-NR) was applied to MS genotyping data. Regions of association were defined based on significance of linkage disequilibrium (LD) blocks. Candidate genes were cross-referenced based on a review of current literature, with attention to molecular function and directly interacting proteins. Supplementary annotations and pathway enrichment scores were generated using The Database for Annotation, Visualization and Integrated Discovery (DAVID). Results The candidate set of 220 MS susceptibility genes prioritized by GWAS-NR was highly enriched with genes involved in biological pathways related to positive regulation of cell, lymphocyte, and leukocyte activation (p=6.1E-15, 1.2E-14, and 5.0E-14, respectively). Novel gene candidates include key regulators of NF-κB signaling and CD4+ T helper type 1 (Th1) and T helper type 17 (Th17) lineages. Conclusions A large subset of MS candidate genes prioritized by GWAS-NR were found to interact in a tractable pathway regulating the NF-κB-mediated induction and infiltration of pro-inflammatory Th1/Th17 T-cell lineages, and maintenance of immune tolerance by T-regulatory cells. This mechanism provides a biological context that potentially links clinical observations in MS to the underlying genetic landscape that may confer susceptibility.

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Section: Resultsmentioning

confidence: 99%

GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis

Hussman¹,

Beecham

Schmidt

et al. 2016

Genes Immun

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“…Our preliminary experiments failed to demonstrate that PBMCs from XIAP-deficient patients secreted larger amounts of IL-18 upon stimulation with LPS and ATP, compared with normal controls. However, recent evidence suggests that XIAP mediates signaling of nucleotidebinding and oligomerization domain 2 (NOD2) in inflammation and innate immunity [29][30][31]. Because NOD2 can activate caspase-1, it is possible that XIAP is involved in inflammasome-mediated IL-18 production.…”

Section: Discussionmentioning

confidence: 99%

Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency

et al. 2014

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X-linked lymphoproliferative syndrome (XLP) is a rare primary immunodeficiency characterized by increased vulnerability to Epstein-Barr virus infection. XLP type 1 is caused by mutations in SH2D1A, whereas X-linked inhibitor of apoptosis (XIAP) encoded by XIAP/BIRC4 is mutated in XLP type 2. In XIAP deficiency, hemophagocytic lymphohistiocytosis (HLH) occurs more frequently and recurrence is common. However, the underlying mechanisms remain mostly unknown. We describe the characteristics of the cytokine profiles of serum samples from 10 XIAP-deficient patients. The concentration of interleukin (IL)-18 was strikingly elevated in the patients presented with HLH, and remained high after the recovery from HLH although levels of other pro-inflammatory cytokines approached the normal range. Longitudinal examination of two patients demonstrated marked exacerbation of IL-18 levels during every occasion of HLH. These findings may suggest the association between HLH susceptibility and high serum IL-18 levels in XIAP deficiency.3

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“…In another study, SHIP suppressed NOD2‐induced NFκB activation in monocytes by blocking the interaction between two crucial components of the NOD2 signaling complex: XIAP and RIP2 (Fig. B, right).…”

Section: Introductionmentioning

confidence: 89%

Regulation of immune cell signaling by SHIP1: A phosphatase, scaffold protein, and potential therapeutic target

2017

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The phosphoinositide phosphatase SHIP is a critical regulator of immune cell activation. Despite considerable study, the mechanisms controlling SHIP activity to ensure balanced cell activation remain incompletely understood. SHIP dampens BCR signaling in part through its association with the inhibitory coreceptor Fc gamma receptor IIB, and serves as an effector for other inhibitory receptors in various immune cell types. The established paradigm emphasizes SHIP's inhibitory receptor‐dependent function in regulating phosphoinositide 3‐kinase signaling by dephosphorylating the phosphoinositide PI(3,4,5)P3; however, substantial evidence indicates that SHIP can be activated independently of inhibitory receptors and can function as an intrinsic brake on activation signaling. Here, we integrate historical and recent reports addressing the regulation and function of SHIP in immune cells, which together indicate that SHIP acts as a multifunctional protein controlled by multiple regulatory inputs, and influences downstream signaling via both phosphatase‐dependent and ‐independent means. We further summarize accumulated evidence regarding the functions of SHIP in B cells, T cells, NK cells, dendritic cells, mast cells, and macrophages, and data suggesting defective expression or activity of SHIP in autoimmune and malignant disorders. Lastly, we discuss the biological activities, therapeutic promise, and limitations of small molecule modulators of SHIP enzymatic activity.

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The Inositol Phosphatase SHIP-1 Inhibits NOD2-Induced NF-κB Activation by Disturbing the Interaction of XIAP with RIP2

Cited by 31 publications

References 54 publications

GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis

GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis

Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency

Regulation of immune cell signaling by SHIP1: A phosphatase, scaffold protein, and potential therapeutic target

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