Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling.

Publisher: Wiley Blackwell Country of Publication: England NLM ID: 8208664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2075 (Electronic) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE

Publication: 2014- : London : Wiley Blackwell
Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-

Nod2 Signaling Adaptor Protein/*metabolism ; Protein Kinase Inhibitors/*pharmacology ; Receptor-Interacting Protein Serine-Threonine Kinase 2/*antagonists & inhibitors ; Receptor-Interacting Protein Serine-Threonine Kinases/*antagonists & inhibitors ; Signal Transduction/*drug effects; Animals ; Cell Line, Tumor ; Female ; Humans ; Inhibitor of Apoptosis Proteins/genetics ; Inhibitor of Apoptosis Proteins/metabolism ; Mice ; Nod2 Signaling Adaptor Protein/genetics ; Receptor-Interacting Protein Serine-Threonine Kinase 2/genetics ; Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Signal Transduction/genetics ; X-Linked Inhibitor of Apoptosis Protein/genetics ; X-Linked Inhibitor of Apoptosis Protein/metabolism

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 vivo NOD2 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.
(© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)

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106169/ZZ14/Z United Kingdom WT_ Wellcome Trust; 102894/Z/13/Z United Kingdom WT_ Wellcome Trust; R01 CA190542 United States CA NCI NIH HHS; MR/N010051/1 United Kingdom MRC_ Medical Research Council; 095751/Z/11/Z United Kingdom WT_ Wellcome Trust; United Kingdom WT_ Wellcome Trust; R21 AI124049 United States AI NIAID NIH HHS

Keywords: XIAP; NOD2 signaling; RIPK2; kinase inhibitor; ubiquitin

0 (Birc4 protein, mouse)
0 (Inhibitor of Apoptosis Proteins)
0 (NOD2 protein, human)
0 (Nod2 Signaling Adaptor Protein)
0 (Nod2 protein, mouse)
0 (Protein Kinase Inhibitors)
0 (X-Linked Inhibitor of Apoptosis Protein)
0 (XIAP protein, human)
EC 2.7.11.1 (RIPK2 protein, human)
EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinase 2)
EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases)
EC 2.7.11.1 (Ripk2 protein, mouse)

Date Created: 20180721 Date Completed: 20190930 Latest Revision: 20220517

20231215

PMC6120666

10.15252/embj.201899372

30026309