RT Journal Article SR Electronic T1 Flotillin-mediated endocytosis and ALIX–syntenin-1–mediated exocytosis protect the cell membrane from damage caused by necroptosis JF Science Signaling JO Sci. Signal. FD American Association for the Advancement of Science SP eaaw3423 DO 10.1126/scisignal.aaw3423 VO 12 IS 583 A1 Fan, Weiliang A1 Guo, Jia A1 Gao, Beichen A1 Zhang, Wenbin A1 Ling, Liucong A1 Xu, Tao A1 Pan, Chenjie A1 Li, Lin A1 Chen, She A1 Wang, Hua A1 Zhang, Jing A1 Wang, Xiaodong YR 2019 UL http://stke.sciencemag.org/content/12/583/eaaw3423.abstract AB 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.