Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation.

Autor:	Garnish SE; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia., Horne CR; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia.; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia., Meng Y; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia., Young SN; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia., Jacobsen AV; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia., Hildebrand JM; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia., Murphy JM; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia.; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Jazyk:	angličtina
Zdroj:	The Biochemical journal [Biochem J] 2024 Sep 04; Vol. 481 (17), pp. 1125-1142.
DOI:	10.1042/BCJ20240255
Abstrakt:	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 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 signalling. We identified 13 compounds - ABT-578, AR-A014418, AZD1480, AZD5363, Idelalisib, Ipatasertib, LJI308, PHA-793887, Rapamycin, Ridaforolimus, SMI-4a, Temsirolimus and Tideglusib - each of which inhibits mammalian target of rapamycin (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 the transport of activated MLKL oligomers to the plasma membrane, where they accumulate into hotspots that permeabilise the lipid bilayer to cause cell death. (© 2024 The Author(s).)
Databáze:	MEDLINE
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