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Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis

Quinten Remijsen (UGent) , Vera Goossens (UGent) , Sasker Grootjans (UGent) , C Van den Haute, Nele Vanlangenakker (UGent) , Yves Dondelinger (UGent) , Ria Roelandt (UGent) , Inge Bruggeman (UGent) , Amanda Gonçalves (UGent) , Mathieu Bertrand (UGent) , et al.
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
Abstract
In human cells, the RIPK1-RIPK3-MLKL-PGAM5-Drp1 axis drives tumor necrosis factor (TNF)-induced necroptosis through mitochondrial fission, but whether this pathway is conserved among mammals is not known. To answer this question, we analyzed the presence and functionality of the reported necroptotic axis in mice. As in humans, knockdown of receptorinteracting kinase-3 (RIPK3) or mixed lineage kinase domain like (MLKL) blocks TNF-induced necroptosis in L929 fibrosarcoma cells. However, repression of either of these proteins did not protect the cells from death, but instead induced a switch from TNF-induced necroptosis to receptor-interacting kinase-1 (RIPK1) kinase-dependent apoptosis. In addition, although mitochondrial fission also occurs during TNF-induced necroptosis in L929 cells, we found that knockdown of phosphoglycerate mutase 5 (PGAM5) and dynamin 1 like protein (Drp1) did not markedly protect the cells from TNF-induced necroptosis. Depletion of Pink1, a reported interactor of both PGAM5 and Drp1, did not affect TNF-induced necroptosis. These results indicate that in these murine cells mitochondrial fission and Pink1 dependent processes, including Pink-Parkin dependent mitophagy, apparently do not promote necroptosis. Our data demonstrate that the core components of the necrosome (RIPK1, RIPK3 and MLKL) are crucial to induce TNF-dependent necroptosis both in human and in mouse cells, but the associated mechanisms may differ between the two species or cell types.
Keywords
apoptosis, TNF, MLKL, RIPK3, necroptosis, MITOCHONDRIAL DEPOLARIZATION, MEDIATES NECROPTOSIS, INTERACTING PROTEIN, CELL-DEATH, TUMOR-NECROSIS-FACTOR, MIXED LINEAGE KINASE, L929 CELLS, COMPLEX, FACTOR RECEPTOR-1, DOMAIN-LIKE

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Citation

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Chicago
Remijsen, Quinten, Vera Goossens, Sasker Grootjans, C Van den Haute, Nele Vanlangenakker, Yves Dondelinger, Ria Roelandt, et al. 2014. “Depletion of RIPK3 or MLKL Blocks TNF-driven Necroptosis and Switches Towards a Delayed RIPK1 Kinase-dependent Apoptosis.” Cell Death & Disease 5.
APA
Remijsen, Q., Goossens, V., Grootjans, S., Van den Haute, C., Vanlangenakker, N., Dondelinger, Y., Roelandt, R., et al. (2014). Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis. CELL DEATH & DISEASE, 5.
Vancouver
1.
Remijsen Q, Goossens V, Grootjans S, Van den Haute C, Vanlangenakker N, Dondelinger Y, et al. Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis. CELL DEATH & DISEASE. 2014;5.
MLA
Remijsen, Quinten, Vera Goossens, Sasker Grootjans, et al. “Depletion of RIPK3 or MLKL Blocks TNF-driven Necroptosis and Switches Towards a Delayed RIPK1 Kinase-dependent Apoptosis.” CELL DEATH & DISEASE 5 (2014): n. pag. Print.
@article{4375631,
  abstract     = {In human cells, the RIPK1-RIPK3-MLKL-PGAM5-Drp1 axis drives tumor necrosis factor (TNF)-induced necroptosis through mitochondrial fission, but whether this pathway is conserved among mammals is not known. To answer this question, we analyzed the presence and functionality of the reported necroptotic axis in mice. As in humans, knockdown of receptorinteracting kinase-3 (RIPK3) or mixed lineage kinase domain like (MLKL) blocks TNF-induced necroptosis in L929 fibrosarcoma cells. However, repression of either of these proteins did not protect the cells from death, but instead induced a switch from TNF-induced necroptosis to receptor-interacting kinase-1 (RIPK1) kinase-dependent apoptosis. In addition, although mitochondrial fission also occurs during TNF-induced necroptosis in L929 cells, we found that knockdown of phosphoglycerate mutase 5 (PGAM5) and dynamin 1 like protein (Drp1) did not markedly protect the cells from TNF-induced necroptosis. Depletion of Pink1, a reported interactor of both PGAM5 and Drp1, did not affect TNF-induced necroptosis. These results indicate that in these murine cells mitochondrial fission and Pink1 dependent processes, including Pink-Parkin dependent mitophagy, apparently do not promote necroptosis. Our data demonstrate that the core components of the necrosome (RIPK1, RIPK3 and MLKL) are crucial to induce TNF-dependent necroptosis both in human and in mouse cells, but the associated mechanisms may differ between the two species or cell types.},
  articleno    = {e1004},
  author       = {Remijsen, Quinten and Goossens, Vera and Grootjans, Sasker and Van den Haute, C and Vanlangenakker, Nele and Dondelinger, Yves and Roelandt, Ria and Bruggeman, Inge and Gon\c{c}alves, Amanda and Bertrand, Mathieu and Baekelandt, V and Takahashi, Nozomi and Vanden Berghe, Tom and Vandenabeele, Peter},
  issn         = {2041-4889},
  journal      = {CELL DEATH \& DISEASE},
  language     = {eng},
  pages        = {8},
  title        = {Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis},
  url          = {http://dx.doi.org/10.1038/cddis.2013.531},
  volume       = {5},
  year         = {2014},
}

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