%0 Journal Article
%A Chauhan, Chanchal
%A Kraemer, Andreas
%A Knapp, Stefan
%A Windheim, Mark
%A Kotlyarov, Alexey
%A Menon, Manoj B
%A Gaestel, Matthias
%T 5-Iodotubercidin sensitizes cells to RIPK1-dependent necroptosis by interfering with NFκB signaling.
%J Cell death discovery
%V 9
%N 1
%@ 2058-7716
%C London
%I Nature Publishing Group
%M DKFZ-2023-01510
%P 262
%D 2023
%X Receptor-interacting protein kinases (RIPK)-1 and -3 play crucial roles in cell fate decisions and are regulated by multiple checkpoint controls. Previous studies have identified IKK1/2- and p38/MK2-dependent checkpoints that phosphorylate RIPK1 at different residues to inhibit its activation. In this study, we investigated TNF-induced death in MAPK-activated protein kinase 2 (MK2)-deficient cells and found that MK2 deficiency or inactivation predominantly leads to necroptotic cell death, even without caspase inhibition. While RIPK1 inhibitors can rescue MK2-deficient cells from necroptosis, inhibiting RIPK3 seems to switch the process to apoptosis. To understand the underlying mechanism of this switch, we screened a library of 149 kinase inhibitors and identified the adenosine analog 5-Iodotubercidin (5-ITu) as the most potent compound that sensitizes MK2-deficient MEFs to TNF-induced cell death. 5-ITu also enhances LPS-induced necroptosis when combined with MK2 inhibition in RAW264.7 macrophages. Further mechanistic studies revealed that 5-ITu induces RIPK1-dependent necroptosis by suppressing IKK signaling in the absence of MK2 activity. These findings highlight the role for the multitarget kinase inhibitor 5-ITu in TNF-, LPS- and chemotherapeutics-induced necroptosis and its potential implications in RIPK1-targeted therapies.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37495567
%R 10.1038/s41420-023-01576-x
%U https://inrepo02.dkfz.de/record/277799