![]() ![]() Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Identification of RIP1 kinase as a specific cellular target of necrostatins. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. A non-canonical PDK1-RSK signal diminishes pro-caspase-8-mediated necroptosis blockade. Phosphorylation-driven assembly of the RIP1–RIP3 complex regulates programmed necrosis and virus-induced inflammation. ![]() Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Death receptor signal transducers: nodes of coordination in immune signaling networks. TNF-α induces two distinct caspase-8 activation pathways. Necroptosis in development, inflammation and disease. The revealing of nanoscale architecture of necrosomes here innovates our understanding of the structural and organizational basis of this signalling hub in cell death. Similarly, apoptosis initiated by enzymatically defective RIP3 requires the formation of rod-shaped mosaics of RIP3 and RIP1 oligomers. Unexpectedly, RIP1 autophosphorylation not only controls the ordered oligomerization of RIP1 but also is required for RIP1-initiated RIP3 homo-oligomerization in correct organization, which is indispensable for the formation of functional rod-shaped mosaics. RIP3 oligomers with sizes of tetramer or above are the domains in mosaics that allow MLKL, recruited by phosphorylated RIP3, to oligomerize for necroptosis. The small (initial) mosaic complexes are round, and the large mosaics are in a rod shape. ![]() Here we use super-resolution microscopy to directly visualize cellular necrosomes as mosaics of RIP1 and RIP3 oligomers. How RIP1/RIP3 amyloidal oligomers assemble functional necrosomes and control cell death is largely unknown. RIP1 and RIP3, cell death mediators, form fibrous amyloids. ![]()
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