RIP3 Induces Apoptosis Independent of Pronecrotic Kinase Activity

Pratyusha Mandal, Scott B. Berger, Sirika Pillay, Kenta Moriwaki, Chunzi Huang, Hongyan Guo, John D. Lich, Joshua Finger, Viera Kasparcova, Bart Votta, Michael Ouellette, Bryan W. King, David Wisnoski, Ami S. Lakdawala, Michael P. DeMartino, Linda N. Casillas, Pamela A. Haile, Clark A. Sehon, Robert W. Marquis, Jason UptonLisa P. Daley-Bauer, Linda Roback, Nancy Ramia, Cole M. Dovey, Jan E. Carette, Francis Ka Ming Chan, John Bertin, Peter J. Gough, Edward S. Mocarski, William J. Kaiser

Research output: Contribution to journalArticlepeer-review

302 Scopus citations


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 aRipoptosome-like platform. This work highlights acommon mechanism unveiling RHIM-driven apoptosis by therapeutic or genetic perturbation of RIP3.

Original languageEnglish (US)
Pages (from-to)481-495
Number of pages15
JournalMolecular Cell
Issue number4
StatePublished - Nov 20 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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