Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation
- Author(s)
- Garnish, SE; Horne, CR; Meng, Y; Young, SN; Jacobsen, AV; Hildebrand, J; Murphy, JM;
- Details
- Publication Year 2024-08-13,Volume 481,Issue #17,Page 1125-1142
- Journal Title
- Biochemical Journal
- Abstract
- Necroptosis is a lytic and pro-inflammatory form of programmed cell death executed by the terminal effector, the MLKL (Mixed Lineage Kinase Domain-like) pseudokinase. Downstream of death and Toll-like receptor stimulation, MLKL is trafficked to the plasma membrane via the Golgi-, actin- and microtubule- machinery, where activated MLKL accumulates until a critical lytic threshold is exceeded and cell death ensues. Mechanistically, MLKL's lytic function relies on disengagement of the N-terminal membrane-permeabilising four-helix bundle (4HB) domain from the central autoinhibitory brace helix: a process that can be experimentally mimicked by introducing the R30E MLKL mutation to induce stimulus-independent cell death. Here, we screened a library of 429 kinase inhibitors for their capacity to block R30E MLKL-mediated cell death, to identify co-effectors in the terminal steps of necroptotic signaling. We identified 13 compounds - ABT-578, AR-A014418, AZD1480, AZD5363, Idelalisib, Ipatasertib, LJ1308, PHA-793887, Rapamycin, Ridaforolimus, SMI-4a, Temsirolimus and Tideglusib - each of which inhibits mTOR signalling or regulators thereof, and blocked constitutive cell death executed by R30E MLKL. Our study implicates mTOR signalling as an auxiliary factor in promoting transport of activated MLKL oligomers to the plasma membrane, where they accumulate into hotspots that permeabilise the lipid bilayer to cause cell death.
- Publisher
- Portland Press
- Keywords
- mechanistic target of rapamycinr; necroptosis; protein kinase; pseudokinase; signalling
- Research Division(s)
- Inflammation
- PubMed ID
- 39136677
- Publisher's Version
- https://doi.org/10.1042/bcj20240255
- Open Access at Publisher's Site
https://doi.org/10.1042/BCJ20240255- Terms of Use/Rights Notice
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Creation Date: 2024-08-23 02:54:11
Last Modified: 2024-09-02 11:00:04