Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
Originalsprog | Engelsk |
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Tidsskrift | The EMBO Journal |
Vol/bind | 37 |
Udgave nummer | 17 |
ISSN | 0261-4189 |
DOI | |
Status | Udgivet - 3 sep. 2018 |
Eksternt udgivet | Ja |
Bibliografisk note
© 2018 The Authors. Published under the terms of the CC BY 4.0 license.
ID: 280716915