Tuning the way to die: implications of membrane perturbations in necroptosis

Abstract Necroptosis is a form of regulated cell death that critically depends on the function of Mixed Lineage Kinase Domain-Like Pseudokinase (MLKL). MLKL activation triggers plasma membrane permeabilization and other cellular processes aimed at preparing necroptotic cells to communicate with its neighbors and stimulate inflammation and immunogenicity. Membrane repair mechanisms play a key role in delaying necroptosis, by compensating the lethal effect of MLKL. Tuning the regulation of MLKL activities and counterbalancing machineries can define cell fate and the way the immune system is activated. Beside necroptosis, other forms of cell death are also notable for their impact on the plasma membrane and their role at engaging the immune system. Understanding the principles that govern plasma membrane reorganization is crucial to regulate their diverse immunological outcomes. Here we review current knowledge about the involvement of MLKL in mediating necroptosis and compare it with other lytic types of cell death.