5-iodotubercidin sensitizes cells to RIPK1-dependent necroptosis by interfering with NFκB signaling

  • Receptor-interacting protein kinases (RIPK) −1 and −3 are master regulators of cell fate decisions in response to diverse stimuli and are subjected to multiple checkpoint controls. Earlier studies have established the presence of distinct IKK1/2 and p38/MK2-dependent checkpoints which suppress RIPK1 activation by directly phosphorylating it at different residues. In the present study, we investigated TNF-induced death in MAPK-activated protein kinase 2 (MK2)-deficient cells and show that MK2-deficiency or inactivation predominantly results in necroptotic cell death, even in the absence of caspase inhibition. While MK2-deficient cells can be rescued from necroptosis by RIPK1 inhibitors, RIPK3 inhibition seems to revert the process triggering apoptosis. To understand the mechanism of this necroptosis switch, we screened a 149-compound kinase inhibitor library for compounds which preferentially sensitize MK2-deficient MEFs to TNF-induced cell death. The most potent inhibitor identified was 5-Iodotubericidin, an adenosine analogue acting as adenosine kinase and protein kinase inhibitor. 5-ITu also potentiated LPS-induced necroptosis when combined with MK2 inhibition in RAW264.7 macrophages. Further mechanistic studies revealed that 5-Iodotubericidin induces RIPK1-dependent necroptosis in the absence of MK2 activity by suppressing IKK signaling. The identification of this role for the multitarget kinase inhibitor 5-ITu in TNF-, LPS- and chemotherapeutics-induced necroptosis will have potential implications in RIPK1-targeted therapies.

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Metadaten
Author:Chanchal ChauhanORCiD, Andreas KrämerORCiDGND, Stefan KnappORCiD, Mark WindheimORCiDGND, Alexey KotlyarovORCiDGND, Manoj Balakrishna MenonORCiDGND, Matthias GaestelORCiDGND
URN:urn:nbn:de:hebis:30:3-731776
DOI:https://doi.org/10.1101/2023.03.03.530727
Parent Title (English):bioRxiv
Document Type:Preprint
Language:English
Date of Publication (online):2023/03/06
Date of first Publication:2023/03/06
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/07/05
Issue:2023.03.03.530727
Page Number:22
HeBIS-PPN:510536751
Institutes:Medizin
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International