Abstract
RIPK2 mediates inflammatory signaling by the bacteria-sensing receptors NOD1 and NOD2. Kinase inhibitors targeting RIPK2 are a proposed strategy to ameliorate NOD-mediated pathologies. Here, we reveal that RIPK2 kinase activity is dispensable for NOD2 inflammatory signaling and show that RIPK2 inhibitors function instead by antagonizing XIAP-binding and XIAP-mediated ubiquitination of RIPK2. We map the XIAP binding site on RIPK2 to the loop between β2 and β3 of the N-lobe of the kinase, which is in close proximity to the ATP-binding pocket. Through characterization of a new series of ATP pocket-binding RIPK2 inhibitors, we identify the molecular features that determine their inhibition of both the RIPK2-XIAP interaction, and of cellular and in vivoNOD2 signaling. Our study exemplifies how targeting of the ATP-binding pocket in RIPK2 can be exploited to interfere with the RIPK2-XIAP interaction for modulation of NOD signaling.
Keywords:
XIAP; NOD2 signaling; RIPK2; kinase inhibitor; ubiquitin.
© 2018 The Authors. Published under the terms of the CC BY 4.0 license.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Female
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Humans
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism
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Mice
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Nod2 Signaling Adaptor Protein / genetics
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Nod2 Signaling Adaptor Protein / metabolism*
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Protein Kinase Inhibitors / pharmacology*
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Receptor-Interacting Protein Serine-Threonine Kinase 2 / antagonists & inhibitors*
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Receptor-Interacting Protein Serine-Threonine Kinase 2 / genetics
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Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism
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Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics
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Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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X-Linked Inhibitor of Apoptosis Protein / genetics
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X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
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Birc4 protein, mouse
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Inhibitor of Apoptosis Proteins
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NOD2 protein, human
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Nod2 Signaling Adaptor Protein
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Nod2 protein, mouse
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Protein Kinase Inhibitors
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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RIPK2 protein, human
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Receptor-Interacting Protein Serine-Threonine Kinase 2
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk2 protein, mouse