Mechanistic analysis of MLKL-driven cell survival

MLKL pseudokinase is a critical executioner of necroptotic cell death. MLKL drives necroptosis by forming pores in the cell membrane. A growing body of data indicates that, in addition to this well-established role, MLKL can promote cell survival in certain contexts. Moreover, pharmacological or genetic MLKL inhibition was shown to suppress in vivo growth of several tumor types. It was found that MLKL protects cancer cells from various cell death-inducing stimuli by promoting autophagy or preserving the mitochondrial function of the cells. It was proposed that both of these MLKL effects prevent parthanatos, a cell death type mediated by hyperactivation of PARP1 and subsequent PARP1-dependent chromosomal DNA degradation. In addition, MLKL was found to protect tumor cells from the death receptor-induced demise and trigger the secretion of the growth-promoting cytokines by the cells. Notably, MLKL-deficient mice are healthy, while pharmacological MLKL inhibitors are not significantly toxic to mice. Hence, targeting MLKL in vivo to block MLKL-dependent cancer cell survival is feasible. The mechanisms of the pro-survival MLKL effects is the subject of this review.