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

Matous Hrdinka; Lisa Schlicher; Bing Dai; Daniel M. Pinkas; Joshua C. Bufton; Sarah Picaud; Jennifer A. Ward; Catherine Rogers; Chalada Suebsuwong; Sameer Nikhar; Gregory D. Cuny; Kilian V.M. Huber; Panagis Filippakopoulos; Alex N. Bullock; Alexei Degterev; Mads Gyrd-Hansen

doi:10.15252/embj.201899372

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

Matous Hrdinka, Lisa Schlicher, Bing Dai, Daniel M. Pinkas, Joshua C. Bufton, Sarah Picaud, Jennifer A. Ward, Catherine Rogers, Chalada Suebsuwong, Sameer Nikhar, Gregory D. Cuny, Kilian V.M. Huber, Panagis Filippakopoulos, Alex N. Bullock, Alexei Degterev^*, Mads Gyrd-Hansen

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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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.

Original language	English
Article number	e99372
Number of pages	16
Journal	EMBO Journal
Volume	37
Issue number	17
Early online date	19 Jul 2018
DOIs	https://doi.org/10.15252/embj.201899372
Publication status	Published - 3 Sept 2018

Keywords

kinase inhibitor
NOD2 signaling
RIPK2
ubiquitin
XIAP

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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, 37(17), Article e99372. https://doi.org/10.15252/embj.201899372

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title = "Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling",

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 = "kinase inhibitor, NOD2 signaling, RIPK2, ubiquitin, XIAP",

author = "Matous Hrdinka and Lisa Schlicher and Bing Dai and Pinkas, {Daniel M.} and Bufton, {Joshua C.} and Sarah Picaud and Ward, {Jennifer A.} and Catherine Rogers and Chalada Suebsuwong and Sameer Nikhar and Cuny, {Gregory D.} and Huber, {Kilian V.M.} and Panagis Filippakopoulos and Bullock, {Alex N.} and Alexei Degterev and Mads Gyrd-Hansen",

year = "2018",

month = sep,

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doi = "10.15252/embj.201899372",

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Hrdinka, M, Schlicher, L, Dai, B, Pinkas, DM, Bufton, JC, Picaud, S, Ward, JA, Rogers, C, Suebsuwong, C, Nikhar, S, Cuny, GD, Huber, KVM, Filippakopoulos, P, Bullock, AN, 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

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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 V.M.

AU - Filippakopoulos, Panagis

AU - Bullock, Alex N.

AU - Degterev, Alexei

AU - Gyrd-Hansen, Mads

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 - kinase inhibitor

KW - NOD2 signaling

KW - RIPK2

KW - ubiquitin

KW - XIAP

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U2 - 10.15252/embj.201899372

DO - 10.15252/embj.201899372

M3 - Article (Academic Journal)

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AN - SCOPUS:85050409574

SN - 0261-4189

VL - 37

JO - EMBO Journal

JF - EMBO Journal

IS - 17

M1 - e99372

ER -

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

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