Figure 4.

MLKL translocation and membrane association induce necroptosis. (A) Scheme of MLKL structure. MLKL contains an N-terminal α-helices domain (NTD), a brace region (BR), and a C-terminals pseudokinase domain (PKD). (B) Upon necroptosis induction, MLKL forms a necrosome with RIPK1 and RIPK3, where it is activated by RIPK3-mediated phosphorylation. The phosphorylation of MLKL leads to release of the BR and NTD, followed by the formation of tetramers and subsequent octamers. After the MLKL octamer is dissociated from the necrosome, it translocates to the plasma membrane to disrupt membrane integrity and induces necroptosis. The membrane association of phosphorylated-MLKL can be regulated by IP kinases IPMK and ITPK1. HSP90 is indispensable for necrosome formation. Necroptosis can be inhibited by MLKL inhibitors NSA, GW806742X and protein Trx1.