Fig. 4: Necroptotic-like cell death operates in three major eukaryotic kingdoms.
From: Regulated cell death in fungi from a comparative immunology perspective
In mammals, necroptosis depends upon the formation of a protein complex termed the necrosome, formed by the RIP1 and RIP3 kinases. The RIP homotypic interaction motif (RHIM) is a short amyloidogenic sequence that mediates necrosome formation. Activated RIPK3 in the necrosome phosphorylates the pseudokinase domain of MLKL, the executioner of necroptosis. Phosphorylated MLKL aggregates and punctures the plasma membrane, forming a transmembrane cation channel, ultimately inducing cell death. The four-helical bundle (4HB) domain plays an essential role in MLKL membrane targeting. An octameric MLKL complex, composed of two tetramers, opens a cation channel to induce necroptotic cell death. The membrane-targeting module has been characterized in immunity-related cell death processes in plants and fungi. In plants, 4HB homologs can be found in some NLRs and in recently characterized plant MLKL-like proteins. These plant and fungal homologs carry distinct names – RPW8 (Resistant to Powdery Mildew) coiled-coil domain (CCRPW8) and HeLo (found in HET-s/LopB) domain. Plant NLRs carrying the CCRPW8 play an important role in the plant immune system, controlling localized necrotic cell death in response to pathogens, termed the hypersensitive response (HR). Some such plant NLRs have been shown to form a pentameric complex named the resistosome to induce HR. The HeLo domain has also been experimentally characterized in fungi. Some fungal NLRs control HeLo-domain cell death effectors through signal transduction involving amyloid-forming domains, some of which appear homologous to mammalian RHIM. HeLo (and CCRPW8) rely on an extreme N-terminal α-helix to attack the plasma membrane. While fungal HeLo domains are shown to act as pore-forming proteins in vitro, it is currently unknown if they form cation channels.
