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

Hrdinka M, Schlicher L, Dai B, Pinkas DM, Bufton JC, Picaud S, Ward JA, Rogers C, Suebsuwong C, Nikhar S, Cuny GD, Huber KV, Filippakopoulos P, Bullock AN, Degterev A, Gyrd-Hansen M
EMBO J 37 (2018)
Cited: 35 times
EuropePMC logo PMID: 30026309

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.

Reviews - 6fu5 mentioned but not cited (1)

  1. Ellagic Acid, Kaempferol, and Quercetin from Acacia nilotica: Promising Combined Drug With Multiple Mechanisms of Action. Al-Nour MY, Ibrahim MM, Elsaman T. Curr Pharmacol Rep 5 255-280 (2019)

Articles - 6fu5 mentioned but not cited (5)

  1. Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling. Hrdinka M, Schlicher L, Dai B, Pinkas DM, Bufton JC, Picaud S, Ward JA, Rogers C, Suebsuwong C, Nikhar S, Cuny GD, Huber KV, Filippakopoulos P, Bullock AN, Degterev A, Gyrd-Hansen M. EMBO J 37 e99372 (2018)
  2. Receptor-interacting protein kinase 2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling inhibitors based on a 3,5-diphenyl-2-aminopyridine scaffold. Suebsuwong C, Dai B, Pinkas DM, Duddupudi AL, Li L, Bufton JC, Schlicher L, Gyrd-Hansen M, Hu M, Bullock AN, Degterev A, Cuny GD. Eur J Med Chem 200 112417 (2020)
  3. A regulatory region on RIPK2 is required for XIAP binding and NOD signaling activity. Heim VJ, Dagley LF, Stafford CA, Hansen FM, Clayer E, Bankovacki A, Webb AI, Lucet IS, Silke J, Nachbur U. EMBO Rep 21 e50400 (2020)
  4. Bioinformatic analysis and functional predictions of selected regeneration-associated transcripts expressed by zebrafish microglia. Issaka Salia O, Mitchell DM. BMC Genomics 21 870 (2020)
  5. Structure shows that the BIR2 domain of E3 ligase XIAP binds across the RIPK2 kinase dimer interface. Lethier M, Huard K, Hons M, Favier A, Brutscher B, Boeri Erba E, Abbott DW, Cusack S, Pellegrini E. Life Sci Alliance 6 e202201784 (2023)


Reviews citing this publication (13)

  1. Pathway paradigms revealed from the genetics of inflammatory bowel disease. Graham DB, Xavier RJ. Nature 578 527-539 (2020)
  2. Kinase inhibition in autoimmunity and inflammation. Zarrin AA, Bao K, Lupardus P, Vucic D. Nat Rev Drug Discov 20 39-63 (2021)
  3. Ubiquitination in the regulation of inflammatory cell death and cancer. Cockram PE, Kist M, Prakash S, Chen SH, Wertz IE, Vucic D. Cell Death Differ 28 591-605 (2021)
  4. Targeting the BIR Domains of Inhibitor of Apoptosis (IAP) Proteins in Cancer Treatment. Cossu F, Milani M, Mastrangelo E, Lecis D. Comput Struct Biotechnol J 17 142-150 (2019)
  5. NOD Signaling and Cell Death. Heim VJ, Stafford CA, Nachbur U. Front Cell Dev Biol 7 208 (2019)
  6. Recent advances in understanding inhibitor of apoptosis proteins. Lalaoui N, Vaux DL. F1000Res 7 F1000 Faculty Rev-1889 (2018)
  7. Regulation of Cell Death and Immunity by XIAP. Jost PJ, Vucic D. Cold Spring Harb Perspect Biol 12 a036426 (2020)
  8. RIPK protein kinase family: Atypical lives of typical kinases. Cuny GD, Degterev A. Semin Cell Dev Biol 109 96-105 (2021)
  9. RIPK2 as a New Therapeutic Target in Inflammatory Bowel Diseases. Honjo H, Watanabe T, Kamata K, Minaga K, Kudo M. Front Pharmacol 12 650403 (2021)
  10. Infection-induced inflammation from specific inborn errors of immunity to COVID-19. Ku CL, Chen IT, Lai MZ. FEBS J 288 5021-5041 (2021)
  11. NOD1, NOD2, and NLRC5 Receptors in Antiviral and Antimycobacterial Immunity. Godkowicz M, Druszczyńska M. Vaccines (Basel) 10 1487 (2022)
  12. Supramolecular Complexes in Cell Death and Inflammation and Their Regulation by Autophagy. Gentle IE. Front Cell Dev Biol 7 73 (2019)
  13. Inborn Errors in the LRR Domain of Nod2 and Their Potential Consequences on the Function of the Receptor. Alipoor SD, Mirsaeidi M. Cells 10 2031 (2021)

Articles citing this publication (16)

  1. Genetic Sequencing of Pediatric Patients Identifies Mutations in Monogenic Inflammatory Bowel Disease Genes that Translate to Distinct Clinical Phenotypes. Ashton JJ, Mossotto E, Stafford IS, Haggarty R, Coelho TAF, Batra A, Afzal NA, Mort M, Bunyan D, Beattie RM, Ennis S. Clin Transl Gastroenterol 11 e00129 (2020)
  2. Human ZBP1 induces cell death-independent inflammatory signaling via RIPK3 and RIPK1. Peng R, Wang CK, Wang-Kan X, Idorn M, Kjaer M, Zhou FY, Fiil BK, Timmermann F, Orozco SL, McCarthy J, Leung CS, Lu X, Bagola K, Rehwinkel J, Oberst A, Maelfait J, Paludan SR, Gyrd-Hansen M. EMBO Rep 23 e55839 (2022)
  3. NOD2 modulates immune tolerance via the GM-CSF-dependent generation of CD103+ dendritic cells. Prescott D, Maisonneuve C, Yadav J, Rubino SJ, Girardin SE, Philpott DJ. Proc Natl Acad Sci U S A 117 10946-10957 (2020)
  4. Pan-cancer analysis reveals RIPK2 predicts prognosis and promotes immune therapy resistance via triggering cytotoxic T lymphocytes dysfunction. Song J, Yang R, Wei R, Du Y, He P, Liu X. Mol Med 28 47 (2022)
  5. RIPK2 is an unfavorable prognosis marker and a potential therapeutic target in human kidney renal clear cell carcinoma. Li D, Tang L, Liu B, Xu S, Jin M, Bo W. Aging (Albany NY) 13 10450-10467 (2021)
  6. XIAP promotes melanoma growth by inducing tumour neutrophil infiltration. Daoud M, Broxtermann PN, Schorn F, Werthenbach JP, Seeger JM, Schiffmann LM, Brinkmann K, Vucic D, Tüting T, Mauch C, Kulms D, Zigrino P, Kashkar H. EMBO Rep 23 e53608 (2022)
  7. Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2. Miller MH, Shehat MG, Tigno-Aranjuez JT. Immunohorizons 4 825-836 (2020)
  8. Isomer-Specific Effects of cis-9,trans-11- and trans-10,cis-12-CLA on Immune Regulation in Ruminal Epithelial Cells. Yang C, Zhu B, Ye S, Fu Z, Li J. Animals (Basel) 11 1169 (2021)
  9. Allele-dependent interaction of LRRK2 and NOD2 in leprosy. Dallmann-Sauer M, Xu YZ, da Costa ALF, Tao S, Gomes TA, Prata RBDS, Correa-Macedo W, Manry J, Alcaïs A, Abel L, Cobat A, Fava VM, Pinheiro RO, Lara FA, Probst CM, Mira MT, Schurr E. PLoS Pathog 19 e1011260 (2023)
  10. Design of pyrido[2,3-d]pyrimidin-7-one inhibitors of receptor interacting protein kinase-2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling. Nikhar S, Siokas I, Schlicher L, Lee S, Gyrd-Hansen M, Degterev A, Cuny GD. Eur J Med Chem 215 113252 (2021)
  11. Regulation of Key Immune-Related Genes in the Heart Following Burn Injury. Wen JJ, Mobli K, Radhakrishnan GL, Radhakrishnan RS. J Pers Med 12 1007 (2022)
  12. A Toolbox for the Generation of Chemical Probes for Baculovirus IAP Repeat Containing Proteins. Schwalm MP, Berger LM, Meuter MN, Vasta JD, Corona CR, Röhm S, Berger BT, Farges F, Beinert SM, Preuss F, Morasch V, Rogov VV, Mathea S, Saxena K, Robers MB, Müller S, Knapp S. Front Cell Dev Biol 10 886537 (2022)
  13. ASKA technology-based pull-down method reveals a suppressive effect of ASK1 on the inflammatory NOD-RIPK2 pathway in brown adipocytes. Takayanagi S, Watanabe K, Maruyama T, Ogawa M, Morishita K, Soga M, Hatta T, Natsume T, Hirano T, Kagechika H, Hattori K, Naguro I, Ichijo H. Sci Rep 11 22009 (2021)
  14. Design, synthesis and biological evaluation of 4-aminoquinoline derivatives as receptor-interacting protein kinase 2 (RIPK2) inhibitors. Fan T, Ji Y, Chen D, Peng X, Ai J, Xiong B. J Enzyme Inhib Med Chem 38 282-293 (2023)
  15. OTUD1 ameliorates cerebral ischemic injury through inhibiting inflammation by disrupting K63-linked deubiquitination of RIP2. Zheng S, Li Y, Song X, Wu M, Yu L, Huang G, Liu T, Zhang L, Shang M, Zhu Q, Gao C, Chen L, Liu H. J Neuroinflammation 20 281 (2023)
  16. Understanding the molecular mechanism of pathogenic variants of BIR2 domain in XIAP-deficient inflammatory bowel disease. Lee J, Sim KM, Kang M, Oh HJ, Choi HJ, Kim YE, Pack CG, Kim K, Kim KM, Oh SH, Kim I, Chang I. Sci Rep 14 853 (2024)


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