Depletion of RIPK3 or MLKL Blocks TNF-driven Necroptosis and Switches Towards a Delayed RIPK1 Kinase-dependent Apoptosis

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2014 Jan 18

PMID 24434512

Citations 112

Authors

Q Remijsen

V Goossens

S Grootjans

C Van den Haute

N Vanlangenakker

Y Dondelinger

R Roelandt

I Bruggeman

A Goncalves

M J M Bertrand

V Baekelandt

N Takahashi

T V Berghe

P Vandenabeele

Affiliations

Soon will be listed here.

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 receptor-interacting 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.

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