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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, C Van den Haute, Nele Vanlangenakker UGent, Yves Dondelinger UGent, Ria Roelandt UGent, Inge Bruggeman UGent, Amanda Gonçalves UGent, Mathieu Bertrand UGent, et al. (2014) CELL DEATH & DISEASE. 5.
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
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
journal title
CELL DEATH & DISEASE
Cell Death Dis.
volume
5
article number
e1004
pages
8 pages
Web of Science type
Article
Web of Science id
000332222700028
JCR category
CELL BIOLOGY
JCR impact factor
5.014 (2014)
JCR rank
50/184 (2014)
JCR quartile
2 (2014)
ISSN
2041-4889
DOI
10.1038/cddis.2013.531
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
4375631
handle
http://hdl.handle.net/1854/LU-4375631
date created
2014-04-30 12:44:03
date last changed
2016-12-21 15:42:22
@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},
  keyword      = {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},
  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},
}

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.