RIP3 induces apoptosis independent of pronecrotic kinase activity.
Receptor-interacting protein kinase 3 (RIP3 or RIPK3) has emerged as a central player in necroptosis and a potential target to control inflammatory disease. Here, three selective small-molecule compounds are shown to inhibit RIP3 kinase-dependent necroptosis, although their therapeutic value is undermined by a surprising, concentration-dependent induction of apoptosis. These compounds interact with RIP3 to activate caspase 8 (Casp8) via RHIM-driven recruitment of RIP1 (RIPK1) to assemble a Casp8-FADD-cFLIP complex completely independent of pronecrotic kinase activities and MLKL. RIP3 kinase-dead D161N mutant induces spontaneous apoptosis independent of compound, whereas D161G, D143N, and K51A mutants, like wild-type, only trigger apoptosis when compound is present. Accordingly, RIP3-K51A mutant mice (Rip3(K51A/K51A)) are viable and fertile, in stark contrast to the perinatal lethality of Rip3(D161N/D161N) mice. RIP3 therefore holds both necroptosis and apoptosis in balance through a Ripoptosome-like platform. This work highlights a common mechanism unveiling RHIM-driven apoptosis by therapeutic or genetic perturbation of RIP3.
Mandal, P; Berger, SB; Pillay, S; Moriwaki, K; Huang, C; Guo, H; Lich, JD; Finger, J; Kasparcova, V; Votta, B; Ouellette, M; King, BW; Wisnoski, D; Lakdawala, AS; DeMartino, MP; Casillas, LN; Haile, PA; Sehon, CA; Marquis, RW; Upton, J; Daley-Bauer, LP; Roback, L; Ramia, N; Dovey, CM; Carette, JE; Chan, FK-M; Bertin, J; Gough, PJ; Mocarski, ES; Kaiser, WJ
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