In Vivo Inhibition of RIPK2 Kinase Alleviates Inflammatory Disease

Tigno-Aranjuez, Justine T.; Benderitter, Pascal; Rombouts, Frederik; Deroose, Frederik; Bai, Xiaodong; Mattioli, Benedetta; Cominelli, Fabio; Pizarro, Theresa T.; Hoflack, Jan; Abbott, Derek W.

doi:10.1074/jbc.m114.591388

Cited by 98 publications

(96 citation statements)

References 44 publications

(48 reference statements)

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“…Despite this, recent work uncovering specific inhibitors of RIPK2 suggested that while initial and acute NF-kB signaling didn’t require kinase activity, optimal NOD-stimulated cytokine and gene expression absolutely require it(11, 19). This finding is supported by our prior study utilizing NextGen RNAseq methods showing that a significant subset of NOD2-induced genes require RIPK2’s kinase activity for optimal expression(25, 26). A key question that remains centers on the scaffolding function of RIPK2’s kinase domain versus its actual kinase activity.…”

Section: Discussionsupporting

confidence: 66%

“…To then further determine the extent of the signaling defect in a manner more quantifiable, NOD2-driven gene expression was studied. Our lab has previously utilized NextGen sequencing technologies to identify the NOD2-driven genes most sensitive to RIPK2’s kinase activity(25, 26). We used these genes as read-outs for gene expression.…”

Section: Resultsmentioning

confidence: 99%

“…While this work was also supported by the fact that a genetic knockin of kinase-dead RIPK2 showed decreased expression, this feature is shared by many kinases in which a kinase-dead variant shows decreased expression(24). In fact, additional pharmacologic studies using a more diverse and specific panel of RIPK2 inhibitors has shown that inhibition of RIPK2 kinase activity does not have a universal role in RIPK2 protein stability(11, 19, 25, 26), thus the role of the kinase activity in RIPK2 protein stability still remains unanswered. A last mystery surrounding the RIPK family of kinases centers on which phosphoacceptor they prefer to phosphorylate.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Synthetic Biology Reveals the Uniqueness of the RIP Kinase Domain

Chirieleison

Kertesy

Abbott

2016

The Journal of Immunology

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The RIP Kinases (RIPKs) play an essential role in inflammatory signaling and inflammatory cell death. However, the function of their kinase activity has been enigmatic, and only recently has kinase domain activity been shown to be crucial for their signal transduction capacity. Despite this uncertainty, the RIPKs have been the subject of intense pharmaceutical development with a number of compounds currently in preclinical testing. In this work, we seek to determine the functional redundancy between the kinase domains of the four major RIPK family members. We find that while RIPK1, RIPK2 and RIPK4 are similar in that they can all activate NF-kB and induce NEMO ubiquitination, only RIPK2 is a dual specificity kinase. Domain swapping experiments showed that the RIPK4 kinase domain could be converted to a dual specificity kinase and is essentially indistinct from RIPK2 in biochemical and molecular activity. Surprisingly, however, replacement of RIPK2’s kinase domain with RIPK4’s did not complement a NOD2 signaling or gene expression induction defect in RIPK2−/− macrophages. These findings suggest that RIPK2’s kinase domain is functionally unique compared to other RIPK family members, and that pharmacologic targeting of RIPK2 can be separated from the other RIPKs.

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Section: Discussionsupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthetic Biology Reveals the Uniqueness of the RIP Kinase Domain

Chirieleison

Kertesy

Abbott

2016

The Journal of Immunology

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“…Lastly, although our overall findings support the potential use of RIP2 targeted therapies in type 2 dominated diseases, how efficacious these will ultimately be, is still uncertain. Previous work, as well as our own, have shown that RIP2 possesses both kinase‐dependent and kinase‐independent effects . We have previously demonstrated the efficacy of pharmacologically targeting RIP2 in a murine model of inflammatory bowel disease and in an MDP‐induced peritonitis model, and since our discovery of RIP2 as a dual‐specificity kinase, many other such kinase inhibitors have been discovered and developed .…”

Section: Discussionmentioning

confidence: 94%

Frontline Science: RIP2 promotes house dust mite–induced allergic airway inflammation

Miller

Shehat

Alcedo

et al. 2018

Journal of Leukocyte Biology

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House dust mites (HDMs) are one of the most significant environmental allergens in the establishment of the so-called "Atopic March." It is known that the immune response to HDM is Th2 dominant, but the innate mechanisms leading to HDM-induced type 2 responses are still not completely understood. A number of innate immune receptors have been implicated in the response to HDM including toll-like receptors, C-type lectin receptors, and protease activated receptors. NOD2 is a member of the NOD-like receptor family, which has been reported to be involved in the establishment of type 2 immunity and in blocking respiratory tolerance. NOD2 mediates its effects through its downstream effector kinase, receptor interacting protein (RIP2). It has not been shown if RIP2 is involved in the innate response to HDM and in the resulting generation of type 2 immunity. Furthermore, the role of RIP2 in modulating allergic airway inflammation has been controversial. In this study, we show that RIP2 is activated in airway epithelial cells in response to HDM and is important for the production of CCL2. Using a murine HDM asthma model, we demonstrate that lung pathology, local airway inflammation, inflammatory cytokines, HDM-specific IgG antibody production, and HDM-specific Th2 responses are all reduced in RIP2 knockout mice compared to WT animals. These data illustrate that RIP2 can be activated by a relevant allergic stimulus and that such activation can contribute to allergic airway inflammation. These findings also suggest that RIP2 inhibitors might have some efficacy in down-regulating the inflammatory response in type 2 dominated diseases.

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“…The development of small molecules capable of modulating NOD1 and NOD2 signaling may also have potential applications in other infectious and inflammatory disease such asthma, arthritis, leprosy, graft versus host disease, and periodontitis which have each been associated with deregulated NOD1 and/or NOD2 signaling (Correa et al, 2012; Jiao et al, 2014; Philpott et al, 2014) but await further functional validation. One of the first successful approaches to modulate NOD2 signaling using small molecules came from the development of kinase inhibitors capable of blocking RIPK2 (Jun et al, 2013; Tigno-Aranjuez et al, 2010; Tigno-Aranjuez et al, 2014) while others identified anti-inflammatory activities for diterpene-based molecules via their ability to specifically block NOD2 signaling (Bielig et al, 2010). More recently, libraries of small molecules were screened identifying lead compounds capable of influencing NOD1 (Khan et al, 2011; Rickard et al, 2013) and NOD2 signaling (Correa et al, 2011; Rickard et al, 2013).…”

Section: Potential For the Therapeutic Modulation Of And Nod1 And Nodmentioning

confidence: 99%

NOD1 and NOD2: Signaling, Host Defense, and Inflammatory Disease

et al. 2014

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Summary The nucleotide-binding oligomerization domain (NOD) proteins, NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and induce pro-inflammatory and anti-microbial responses. Here we discuss recent developments about the mechanisms by which NOD1 and NOD2 are activated by bacterial ligands, the regulation of their signaling pathways, and their role in host defense and inflammatory disease. Several routes for the entry of peptidoglycan ligands to the host cytosol to trigger activation of NOD1 and NOD2 have been elucidated. Furthermore, genetic screens and biochemical analyses have revealed mechanisms that regulate NOD1 and NOD2 signaling. Finally, recent studies suggest several mechanisms to account for the link between NOD2 mutations and susceptibility to Crohn’s disease. Further understanding of NOD1 and NOD2 should provide new insight into the pathogenesis of disease and the development of new strategies to treat inflammatory and infectious disorders.

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In Vivo Inhibition of RIPK2 Kinase Alleviates Inflammatory Disease

Cited by 98 publications

References 44 publications

Synthetic Biology Reveals the Uniqueness of the RIP Kinase Domain

Synthetic Biology Reveals the Uniqueness of the RIP Kinase Domain

Frontline Science: RIP2 promotes house dust mite–induced allergic airway inflammation

NOD1 and NOD2: Signaling, Host Defense, and Inflammatory Disease

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