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2016 ; 23
(7
): 1185-97
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Evolutionary divergence of the necroptosis effector MLKL
#MMPMID26868910
Tanzer MC
; Matti I
; Hildebrand JM
; Young SN
; Wardak A
; Tripaydonis A
; Petrie EJ
; Mildenhall AL
; Vaux DL
; Vince JE
; Czabotar PE
; Silke J
; Murphy JM
Cell Death Differ
2016[Jul]; 23
(7
): 1185-97
PMID26868910
show ga
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.
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