Extended Data Fig. 10: Model of the assembly and function of mosaic RIP1-RIP3 rods.
From: Mosaic composition of RIP1–RIP3 signalling hub and its role in regulating cell death
a, A hypothetic model of RIP1-RIP3 mosaics: (I) Bidirectional β sheets resulted from RHIM-dependent RIP1/RIP3 homo- or hetero-interactions; (II) The β sheets further form helical necrosome rods with about 47 nm in width and 33 nm in pitch length; (III) RIP1/RIP3 homo-oligomers distribute heterogeneously in the rod-shaped necrosome, exhibiting a mosaic pattern. b, Upon necroptosis stimuli, RIP1 is autophosphorylated and this modification retains RIP1 assembly in a proper manner. Ordered RIP1 interaction initiates ordered recruitment of downstream RIP3, leading to the formation of helical rod-shaped necrosomes. Necrosomal RIP1- and RIP3-homo-oligomers distribute as a mosaic pattern, and RIP3 oligomers with sizes equal to or more than tetramer license phosphorylated MLKL to oligomerize for necroptosis. RHIM domain-mediated interaction rather than RIP3 autophosphorylation/MLKL recruitment is indispensable for the formation of rod-shaped necrosomes. In addition, the mosaic RIP1-RIP3 rods are essential for apoptosis by recruiting FADD/Caspase-8 when RIP3 kinase activity was eliminated by GSK’872 or by kinase-dead mutations. Disrupting the ordered RIP1-RIP3 rod-shaped structures could impair the recruitment/activation of downstream molecules. Thus, the ordered RIP1-RIP3 mosaic rod functions as a bidirectional module for the signaling of necroptosis and apoptosis under certain conditions.
