What are the mechanisms of necroptosis?

Necroptosis relies on the presence of the protein RIPK3 (Receptor-Interacting Protein Kinase 3), along with its substrate MLKL (Mixed Lineage Kinase Domain-Like protein). Necroptosis begins when immune signals like Fas, LPS, and TNF trigger the activation of RIPK3, which then phosphorylates MLKL (at specific sites such as S345 in mice or T357 and S358 in humans). Once phosphorylated, MLKL exposes an N-terminal 4-helix bundle (NB) domain and a central brace region, allowing it to form homo-oligomers and bind to phosphatidylinositol phosphate (PIP) species on the inner leaflet of the plasma membrane. This disrupts the inner side of the cell membrane’s integrity. While RIPK3 and MLKL are crucial for programmed cell death, necroptosis only occurs in specific tissues that express these proteins.