Molecular Cell
Volume 56, Issue 4, 20 November 2014, Pages 481-495
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Article
RIP3 Induces Apoptosis Independent of Pronecrotic Kinase Activity

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Highlights

  • RIP3 kinase inhibitors block necroptosis but induce apoptosis

  • This apoptosis requires RHIM-dependent RIP1/FADD/cFLIPL/caspase 8 complex formation

  • RIP3 kinase domain suppresses RHIM signaling independent of kinase activity

  • RIP3 K51A kinase-dead knockin mice are viable, fertile and immunocompetent

Summary

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 (Rip3K51A/K51A) are viable and fertile, in stark contrast to the perinatal lethality of Rip3D161N/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.

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