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Mol Cell. 2014 Nov 20;56(4):481-95. doi: 10.1016/j.molcel.2014.10.021. Epub 2014 Nov 20.

RIP3 induces apoptosis independent of pronecrotic kinase activity.

Author information

1
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
2
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
3
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Department of Pathology, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01605, USA.
5
Molecular Discovery Research, Platform Technologies and Science, GlaxoSmithKline, Collegeville, PA 19426, USA.
6
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
7
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: mocarski@emory.edu.
8
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: wkaiser@emory.edu.

Abstract

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.

PMID:
25459880
PMCID:
PMC4512186
DOI:
10.1016/j.molcel.2014.10.021
[Indexed for MEDLINE]
Free PMC Article

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