Lysosomal MLKL is balanced by ESCRT to control cell death

Mixed lineage kinase-like (MLKL) is activated by RHIM-domain containing kinase (RIPK)3 to permeabilize the plasma-membrane and execute necroptosis, a form of regulated necrosis. We found that MLKL is activated in an atypical, RIPK3- and necroptosis-independent manner downstream of Toll-like receptor 3, resulting in its translocation to lysosomes and lysosomal membrane permeabilization. Damaged lysosomes then undergo exocytosis, leading to the integration of lysosomal MLKL into the plasma-membrane to trigger cell death. The ESCRT-machinery can repair damaged lysosomes and counteract cell death by packing lysosomal MLKL into intraluminal vesicles, which are subsequently released as extracellular vesicles. In this way, ESCRT-machinery balances life and death decisions by preventing lysosomal MLKL to reach its killing destination, which is the plasma-membrane.