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
  • 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: [email protected].
  • 8. Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: [email protected].
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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