Fig. 1

Necroptosis is triggered downstream of death domain receptors (e.g., TNFR and Fas) and Toll-like receptor (TLR)-4 or TLR3. Upon activation, these receptors recruit the adapter proteins FADD, TRADD, and TRIF, which interact with RIPK1 and caspase-8 or -10. First, RIPK1 is ubiquitylated by IAPs, keeping it nonfunctional and enabling proinflammatory downstream activity via NFκB. After detection of a “death signal”, RIPK1 is deubiquitylated by CYLD and can thus recruit RIPK3. The RIPK1/RIP3 complex recruits and phosphorylates MLKL. In the presence of highly phosphorylated inositol phosphate (IP₆), phosphorylated MLKL oligomerizes, thus forming the necrosome. MLKL oligomers translocate to phosphatidylinositol phosphate (PIP)-rich patches in the plasma membrane and form large pores. Ultimately, MLKL pores lead to necroptotic cell death by allowing ion influx, cell swelling, and membrane lysis followed by the uncontrollable release of intracellular material. The cytosolic nucleic acid sensors RIG-I and cGAS/STING also contribute to necroptotic cell death, as they induce IFN-I and TNFα and thus promote necroptosis via an autocrine feedback loop. Downstream of TNFR or TLR engagement, active caspase-8 cleaves the cytokine blocker N4BP1, thus promoting an increase in cytokine release. Once activated, RIPK3 phosphorylates the pyruvate dehydrogenase complex (PDC) in mitochondria and promotes aerobic respiration and mitochondrial ROS production. In the presence of cytosolic DNA released from infecting microbes, DNA-dependent activator of IFN regulatory factor (DAI) recruits RIPK3 and thus bypasses RIPK1 for activation of MLKL and formation of the necrosome complex