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

被引：172

作者：

Remijsen, Q. ^{[1
,2
]}

Goossens, V. ^{[1
,2
]}

Grootjans, S. ^{[1
,2
]}

Van den Haute, C. ^{[3
]}

Vanlangenakker, N. ^{[1
,2
]}

Dondelinger, Y. ^{[1
,2
]}

Roelandt, R. ^{[1
,2
]}

Bruggeman, I. ^{[1
,2
]}

Goncalves, A. ^{[4
]}

Bertrand, M. J. M. ^{[1
,2
]}

Baekelandt, V. ^{[3
]}

Takahashi, N. ^{[1
,2
]}

Vanden Berghe, Tom ^{[1
,2
]}

Vandenabeele, P. ^{[1
,2
]}

机构：

[1] Univ Ghent VIB, Mol Signaling & Cell Death Unit, Inflammat Res Ctr, B-9052 Ghent, Belgium

[2] Univ Ghent, Dept Biomed Mol Biol, Mol Signaling & Cell Death Unit, B-9052 Ghent, Belgium

[3] Katholieke Univ Leuven, Ctr Mol Med, Lab Neurobiol & Gene Therapy, Louvain, Belgium

[4] Univ Ghent VIB, Microscopy Core Facil, Inflammat Res Ctr, B-9052 Ghent, Belgium

来源：

CELL DEATH & DISEASE | 2014年 / 5卷

关键词：

RIPK3; MLKL; TNF; apoptosis; necroptosis; TUMOR-NECROSIS-FACTOR; MIXED LINEAGE KINASE; CELL-DEATH; INTERACTING PROTEIN; MITOCHONDRIAL DEPOLARIZATION; MEDIATES NECROPTOSIS; FACTOR RECEPTOR-1; DOMAIN-LIKE; L929; CELLS; COMPLEX;

D O I：

10.1038/cddis.2013.531

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：e1004 / e1004

页数：8

共 41 条

[1] PINK1 protects against cell death induced by mitochondrial depolarization, by phosphorylating Bcl-xL and impairing its pro-apoptotic cleavage [J].