2.3.2 Kinases MLKL (Mixed lineage kinase domain-like protein), RIPK1 and RIPK3 (receptor-interacting protein kinases 1 and 3)
Annkathrin Koch et al 54 proposed that if cystathionase was blocked with zVAD.fmk (TBZ), the combination therapy of Smac mimicking BV6 and TRAIL induced BL necrotic apoptosis. The higher the expression of MLKL (mixed lineage kinase domain-like protein), the better the therapeutic effect of TBZ on BL cells, confirming that MLKL expression is one of the influencing factors of TBZ treatment on BL cells. Knockdown of MLKL in BL-2, RAMOS, Seraphine, and BL-30 cells showed that cell death was completely inhibited, suggesting that its mediated cell death was heavily dependent on MLKL. Necroptosis is based on the generation of necrosome, the kinase MLKL, RIPK1 and RIPK3 (receptor-interacting protein kinases 1 and 3) constitute the necrosome 55, the place phosphorylation of MLKL and RIPK1 is a necessary link in apoptosis. MLKL is a direct provider of RIPK3 and its phosphorylation allows MLKL to oligomerize and translocate at the plasma membrane, thereby binding it to the membrane and inflicting its dying 56. In BL cell lines, expression of TRAIL-R1/2 57, a Smac mimic that binds to TRAIL (TNF-related apoptosis-inducing ligand), prompts cysteinase-non-dependent necrotic cell dying in an MLKL-dependent manner after cysteinase inhibition.