necrosome

The necrosome is a cytosolic protein complex that mediates necroptosis, a regulated form of necrotic cell death. The core components are receptor-interacting protein kinase 1 (RIPK1) and RIPK3, which interact through RHIM domains; in many models, mixed lineage kinase domain-like protein (MLKL) is recruited and phosphorylated by RIPK3 to execute necroptosis. Necrosome formation is favored when tumor necrosis factor (TNF) signaling occurs and caspase-8 activity is inhibited or absent, shifting the cell death program from apoptosis to necroptosis.

In canonical TNF signaling, RIPK1 is recruited to complex I at the TNF receptor and becomes ubiquitinated, promoting survival signaling. Following deubiquitination of RIPK1 or failure to activate caspase-8, RIPK1 disengages from complex I and forms the cytosolic necrosome with RIPK3. ZBP1 can also trigger RIPK3 recruitment in response to viral infection or other stress. Within the necrosome, RIPK1 and RIPK3 activate by phosphorylation; RIPK3 then phosphorylates MLKL, which oligomerizes and translocates to the plasma membrane to disrupt integrity, causing cell lysis and release of intracellular contents that stimulate inflammation.

Regulation of the necrosome involves ubiquitination, deubiquitination, phosphorylation, and proteasomal degradation. Inhibitors such as necrostatin-1 target RIPK1 kinase activity to prevent necroptosis; other inhibitors target RIPK3 or MLKL. Because necroptosis can amplify inflammation, the necrosome is studied in contexts such as ischemia-reperfusion injury, neurodegenerative diseases, and inflammatory disorders.