Direct Activation of Human MLKL by a Select Repertoire of Inositol Phosphate Metabolites.

McNamara DE, Dovey CM, Hale AT, Quarato G, Grace CR, Guibao CD, Diep J, Nourse A, Cai CR, Wu H, Kalathur RC, Green DR, York JD, Carette JE, Moldoveanu T
Cell Chem Biol. 2019 26 (6): 863-877.e7

PMID: 31031142 · PMCID: PMC6588482 · DOI:10.1016/j.chembiol.2019.03.010

Necroptosis is an inflammatory form of programmed cell death executed through plasma membrane rupture by the pseudokinase mixed lineage kinase domain-like (MLKL). We previously showed that MLKL activation requires metabolites of the inositol phosphate (IP) pathway. Here we reveal that I(1,3,4,6)P, I(1,3,4,5,6)P, and IP promote membrane permeabilization by MLKL through directly binding the N-terminal executioner domain (NED) and dissociating its auto-inhibitory region. We show that IP and inositol pentakisphosphate 2-kinase (IPPK) are required for necroptosis as IPPK deletion ablated IP production and inhibited necroptosis. The NED auto-inhibitory region is more extensive than originally described and single amino acid substitutions along this region induce spontaneous necroptosis by MLKL. Activating IPs bind three sites with affinity of 100-600 μM to destabilize contacts between the auto-inhibitory region and NED, thereby promoting MLKL activation. We therefore uncover MLKL's activating switch in NED triggered by a select repertoire of IP metabolites.

Copyright © 2019 Elsevier Ltd. All rights reserved.

MeSH Terms (8)

Animals Cell Survival HT29 Cells Humans Inositol Phosphates Protein Kinases Sf9 Cells Spodoptera

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