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

Chauhan, Chanchal; Kraemer, Andreas; Knapp, Stefan; Windheim, Mark; Kotlyarov, Alexey; Menon, Manoj B.; Gaestel, Matthias

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.

RECEPTOR-interacting proteins; PROTEIN kinases; CELL death; KINASE inhibitors; CASPASES

Cell Death Discovery, 2023, Vol 9, Issue 1, p1

2058-7716

Academic Journal

10.1038/s41420-023-01576-x