Necroptosis: Pathway diversity and characteristics

Regulated cell death is a physiological process that controls organismal homeostasis. Deregulation of cell death can lead to the development of a number of human diseases and tissue damage. Apoptosis is a best-known model of caspase-dependent regulated cell death, but recently necroptosis has garnered a lot of attention as a form of regulated cell death not mediated by caspases. Different stimuli can trigger necroptosis, and all of them converge at the activation of the protein kinase RIP3 (receptor-interacting protein 3) and the pseudokinase MLKL (mixed lineage kinase domain-like). Necroptosis activation relies on the unique protein-interaction motif RHIM (RIP homology interaction motif). Different RHIM-containing proteins (RIP1, DAI and TRIF) transduce necroptotic signals from the cell death trigger to the cell death mediators RIP3-MLKL. RIP1 has a particularly important and complex role in necroptotic cell death regulation ranging from cell death activation to inhibition, often in a cell type and context dependent fashion.