Small molecule inhibitors reveal an indispensable scaffolding role of RIPK 2 in NOD 2 signaling
| Autor: | Sarah Picaud, Sameer Nikhar, Gregory D. Cuny, Chalada Suebsuwong, Panagis Filippakopoulos, Mads Gyrd-Hansen, Alexei Degterev, Daniel M. Pinkas, Lisa Schlicher, Alex N. Bullock, Joshua C. Bufton, Bing Dai, Kilian Huber, Jennifer A. Ward, Catherine Rogers, Matous Hrdinka |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
RIPK2 kinase inhibitor NOD2 signaling Immunology Nod2 Signaling Adaptor Protein X-Linked Inhibitor of Apoptosis Protein Article General Biochemistry Genetics and Molecular Biology Inhibitor of Apoptosis Proteins Mice 03 medical and health sciences XIAP Ubiquitin Receptor-Interacting Protein Serine-Threonine Kinase 2 Cell Line Tumor ubiquitin Animals Humans Kinase activity Binding site Receptor Protein Kinase Inhibitors Molecular Biology General Immunology and Microbiology biology Kinase General Neuroscience Articles Small molecule Cell biology 030104 developmental biology Receptor-Interacting Protein Serine-Threonine Kinases biology.protein Autophagy & Cell Death Female Signal Transduction |
| Zdroj: | Hrdinka, M, Schlicher, L, Dai, B, Pinkas, D M, Bufton, J C, Picaud, S, Ward, J A, Rogers, C, Suebsuwong, C, Nikhar, S, Cuny, G D, Huber, K V M, Filippakopoulos, P, Bullock, A N, Degterev, A & Gyrd-Hansen, M 2018, ' Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling ', EMBO Journal, vol. 37, no. 17, e99372 . https://doi.org/10.15252/embj.201899372 The EMBO Journal |
| ISSN: | 1460-2075 0261-4189 |
| DOI: | 10.15252/embj.201899372 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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