TY  - JOUR
AU  - Chauhan, Chanchal
AU  - Kraemer, Andreas
AU  - Knapp, Stefan
AU  - Windheim, Mark
AU  - Kotlyarov, Alexey
AU  - Menon, Manoj B
AU  - Gaestel, Matthias
TI  - 5-Iodotubercidin sensitizes cells to RIPK1-dependent necroptosis by interfering with NFκB signaling.
JO  - Cell death discovery
VL  - 9
IS  - 1
SN  - 2058-7716
CY  - London
PB  - Nature Publishing Group
M1  - DKFZ-2023-01510
SP  - 262
PY  - 2023
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:37495567
DO  - DOI:10.1038/s41420-023-01576-x
UR  - https://inrepo02.dkfz.de/record/277799
ER  -