Evolutionary divergence of the necroptosis effector MLKL

The pseudokinase, MLKL (mixed-lineage kinase domain-like), is the most terminal obligatory component of the necroptosis cell death pathway known. Phosphorylation of the MLKL pseudokinase domain by the protein kinase, receptor interacting protein kinase-3 (RIPK3), is known to be the key step in MLKL...

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Published in:	Cell death and differentiation Vol. 23; no. 7; pp. 1185 - 1197
Main Authors:	Tanzer, M C, Matti, I, Hildebrand, J M, Young, S N, Wardak, A, Tripaydonis, A, Petrie, E J, Mildenhall, A L, Vaux, D L, Vince, J E, Czabotar, P E, Silke, J, Murphy, J M
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-07-2016 Nature Publishing Group
Subjects:	631/45/607/275 631/45/612 82/80 96/106 96/109 96/95 Animals Anura Apoptosis Apoptosis - drug effects Biochemistry Biomedical and Life Sciences Cell Biology Cell Cycle Analysis Cell death Cell division Cell Line Cell Membrane Permeability - drug effects Chickens Evolution, Molecular Fibroblasts HeLa Cells Horses HT29 Cells Humans Kinases Life Sciences Liposomes - metabolism Medical research Mice Necrosis - genetics Original Paper Phosphorylation Phosphorylation - drug effects Protein Domains Protein Kinases - chemistry Protein Kinases - genetics Protein Kinases - metabolism Proteins Receptor-Interacting Protein Serine-Threonine Kinases - metabolism Recombinant Proteins - biosynthesis Recombinant Proteins - chemistry Recombinant Proteins - pharmacology Stem Cells Tumor necrosis factor-TNF Australia
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Summary:	The pseudokinase, MLKL (mixed-lineage kinase domain-like), is the most terminal obligatory component of the necroptosis cell death pathway known. Phosphorylation of the MLKL pseudokinase domain by the protein kinase, receptor interacting protein kinase-3 (RIPK3), is known to be the key step in MLKL activation. This phosphorylation event is believed to trigger a molecular switch, leading to exposure of the N-terminal four-helix bundle (4HB) domain of MLKL, its oligomerization, membrane translocation and ultimately cell death. To examine how well this process is evolutionarily conserved, we analysed the function of MLKL orthologues. Surprisingly, and unlike their mouse, horse and frog counterparts, human, chicken and stickleback 4HB domains were unable to induce cell death when expressed in murine fibroblasts. Forced dimerization of the human MLKL 4HB domain overcame this defect and triggered cell death in human and mouse cell lines. Furthermore, recombinant proteins from mouse, frog, human and chicken MLKL, all of which contained a 4HB domain, permeabilized liposomes, and were most effective on those designed to mimic plasma membrane composition. These studies demonstrate that the membrane-permeabilization function of the 4HB domain is evolutionarily conserved, but reveal that execution of necroptotic death by it relies on additional factors that are poorly conserved even among closely related species.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	1350-9047 1476-5403
DOI:	10.1038/cdd.2015.169