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RIP3 induces apoptosis independent of pronecrotic kinase activity.

Publication ,  Journal Article
Mandal, P; Berger, SB; Pillay, S; Moriwaki, K; Huang, C; Guo, H; Lich, JD; Finger, J; Kasparcova, V; Votta, B; Ouellette, M; King, BW ...
Published in: Mol Cell
November 20, 2014

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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Published In

Mol Cell

DOI

EISSN

1097-4164

Publication Date

November 20, 2014

Volume

56

Issue

4

Start / End Page

481 / 495

Location

United States

Related Subject Headings

  • Receptor-Interacting Protein Serine-Threonine Kinases
  • RNA-Binding Proteins
  • Protein Kinase Inhibitors
  • Nuclear Pore Complex Proteins
  • Necrosis
  • NIH 3T3 Cells
  • Mice, Transgenic
  • Mice
  • Humans
  • HT29 Cells
 

Citation

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Mandal, P., Berger, S. B., Pillay, S., Moriwaki, K., Huang, C., Guo, H., … Kaiser, W. J. (2014). RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell, 56(4), 481–495. https://doi.org/10.1016/j.molcel.2014.10.021
Mandal, Pratyusha, Scott B. Berger, Sirika Pillay, Kenta Moriwaki, Chunzi Huang, Hongyan Guo, John D. Lich, et al. “RIP3 induces apoptosis independent of pronecrotic kinase activity.Mol Cell 56, no. 4 (November 20, 2014): 481–95. https://doi.org/10.1016/j.molcel.2014.10.021.
Mandal P, Berger SB, Pillay S, Moriwaki K, Huang C, Guo H, et al. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell. 2014 Nov 20;56(4):481–95.
Mandal, Pratyusha, et al. “RIP3 induces apoptosis independent of pronecrotic kinase activity.Mol Cell, vol. 56, no. 4, Nov. 2014, pp. 481–95. Pubmed, doi:10.1016/j.molcel.2014.10.021.
Mandal P, Berger SB, Pillay S, Moriwaki K, Huang C, Guo H, Lich JD, Finger J, Kasparcova V, Votta B, Ouellette M, King BW, Wisnoski D, Lakdawala AS, DeMartino MP, Casillas LN, Haile PA, Sehon CA, Marquis RW, Upton J, Daley-Bauer LP, Roback L, Ramia N, Dovey CM, Carette JE, Chan FK-M, Bertin J, Gough PJ, Mocarski ES, Kaiser WJ. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell. 2014 Nov 20;56(4):481–495.
Journal cover image

Published In

Mol Cell

DOI

EISSN

1097-4164

Publication Date

November 20, 2014

Volume

56

Issue

4

Start / End Page

481 / 495

Location

United States

Related Subject Headings

  • Receptor-Interacting Protein Serine-Threonine Kinases
  • RNA-Binding Proteins
  • Protein Kinase Inhibitors
  • Nuclear Pore Complex Proteins
  • Necrosis
  • NIH 3T3 Cells
  • Mice, Transgenic
  • Mice
  • Humans
  • HT29 Cells