LAUSR

Two independent trafficking pathways remove phosphorylated MLKL from the plasma membrane to avert necroptosis. Exit the necroptosis executioner In cells dying by necroptosis, the pseudokinase MLKL becomes phosphorylated and competent to rupture the plasma membrane. However, the appearance of phosphorylated MLKL does not always lead to necroptosis, prompting Fan et al. to investigate how the activity of this necroptosis executioner is suppressed. They found that phosphorylated MLKL could be directed by flotillin-1 and flotillin-2 into lipid rafts and, subsequently, lysosomes. In addition, phosphorylated MLKL could be ejected from cells in exosomes in a pathway dependent on the ESCRT proteins ALIX and syntenin-1. These mechanisms may be safeguards to ensure that only signals of sufficient intensity induce necroptosis. Necroptosis is a form of regulated necrosis that is implicated in various human diseases including Alzheimer’s disease. Necroptosis requires the translocation of the pseudokinase MLKL from the cytosol to the plasma membrane after its phosphorylation by the kinase RIPK3. Using protein cross-linking followed by affinity purification, we detected the lipid raft–associated proteins flotillin-1 and flotillin-2 and the ESCRT-associated proteins ALIX and syntenin-1 in membrane-localized MLKL immunoprecipitates. Phosphorylated MLKL was removed from membranes through either flotillin-mediated endocytosis followed by lysosomal degradation or ALIX–syntenin-1–mediated exocytosis. Thus, cells undergoing necroptosis need to overcome these independent suppressive mechanisms before plasma membrane disruption can occur.