Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling. / Hrdinka, Matous; Schlicher, Lisa; Dai, Bing; Pinkas, Daniel M; Bufton, Joshua C; Picaud, Sarah; Ward, Jennifer A; Rogers, Catherine; Suebsuwong, Chalada; Nikhar, Sameer; Cuny, Gregory D; Huber, Kilian Vm; Filippakopoulos, Panagis; Bullock, Alex N; Degterev, Alexei; Gyrd-Hansen, Mads.
In: The EMBO Journal, Vol. 37, No. 17, 03.09.2018.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling
AU - Hrdinka, Matous
AU - Schlicher, Lisa
AU - Dai, Bing
AU - Pinkas, Daniel M
AU - Bufton, Joshua C
AU - Picaud, Sarah
AU - Ward, Jennifer A
AU - Rogers, Catherine
AU - Suebsuwong, Chalada
AU - Nikhar, Sameer
AU - Cuny, Gregory D
AU - Huber, Kilian Vm
AU - Filippakopoulos, Panagis
AU - Bullock, Alex N
AU - Degterev, Alexei
AU - Gyrd-Hansen, Mads
N1 - © 2018 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2018/9/3
Y1 - 2018/9/3
N2 - 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.
AB - 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.
KW - Animals
KW - Cell Line, Tumor
KW - Female
KW - Humans
KW - Inhibitor of Apoptosis Proteins/genetics
KW - Mice
KW - Nod2 Signaling Adaptor Protein/genetics
KW - Protein Kinase Inhibitors/pharmacology
KW - Receptor-Interacting Protein Serine-Threonine Kinase 2/antagonists & inhibitors
KW - Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors
KW - Signal Transduction/drug effects
KW - X-Linked Inhibitor of Apoptosis Protein/genetics
U2 - 10.15252/embj.201899372
DO - 10.15252/embj.201899372
M3 - Journal article
C2 - 30026309
VL - 37
JO - E M B O Journal
JF - E M B O Journal
SN - 0261-4189
IS - 17
ER -
ID: 280716915