2. Academic Validation
  3. RIP3 induces apoptosis independent of pronecrotic kinase activity

RIP3 induces apoptosis independent of pronecrotic kinase activity

  • Mol Cell. 2014 Nov 20;56(4):481-95. doi: 10.1016/j.molcel.2014.10.021.
Pratyusha Mandal 1,  Scott B Berger 2,  Sirika Pillay 3,  Kenta Moriwaki 4,  Chunzi Huang 1,  Hongyan Guo 1,  John D Lich 2,  Joshua Finger 2,  Viera Kasparcova 2,  Bart Votta 2,  Michael Ouellette 5,  Bryan W King 5,  David Wisnoski 5,  Ami S Lakdawala 5,  Michael P DeMartino 2,  Linda N Casillas 2,  Pamela A Haile 2,  Clark A Sehon 2,  Robert W Marquis 2,  Jason Upton 6,  Lisa P Daley-Bauer 1,  Linda Roback 1,  Nancy Ramia 4,  Cole M Dovey 3,  Jan E Carette 3,  Francis Ka-Ming Chan 4,  John Bertin 2,  Peter J Gough 2,  Edward S Mocarski 7,  William J Kaiser 8
Affiliations

Affiliations

  • 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.
PMID: 25459880 DOI: 10.1016/j.molcel.2014.10.021
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.

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