Format

Send to

Choose Destination
Cell Rep. 2017 Apr 4;19(1):175-187. doi: 10.1016/j.celrep.2017.03.024.

Necroptosis Execution Is Mediated by Plasma Membrane Nanopores Independent of Calcium.

Author information

1
Interfaculty Institute of Biochemistry, Tübingen University, 72076 Tübingen, Germany. Electronic address: uris.ros@ifib.uni-tuebingen.de.
2
Interfaculty Institute of Biochemistry, Tübingen University, 72076 Tübingen, Germany.
3
Institute of Experimental Immunology, University of Zürich, 8057 Zürich, Switzerland.
4
Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
5
Interfaculty Institute of Biochemistry, Tübingen University, 72076 Tübingen, Germany; Max-Planck Institute for Intelligent Systems, 70569 Stuttgart, Germany. Electronic address: ana.garcia@uni-tuebingen.de.

Abstract

Necroptosis is a form of regulated necrosis that results in cell death and content release after plasma membrane permeabilization. However, little is known about the molecular events responsible for the disruption of the plasma membrane. Here, we find that early increase in cytosolic calcium in TNF-induced necroptosis is mediated by treatment with a Smac mimetic via the TNF/RIP1/TAK1 survival pathway. This does not require the activation of the necrosome and is dispensable for necroptosis. Necroptosis induced by the activation of TLR3/4 pathways does not trigger early calcium flux. We also demonstrate that necroptotic plasma membrane rupture is mediated by osmotic forces and membrane pores around 4 nm in diameter. This late permeabilization step represents a hallmark in necroptosis execution that is cell and treatment independent and requires the RIP1/RIP3/MLKL core. In support of this, treatment with osmoprotectants reduces cell damage in an in vivo necroptosis model of ischemia-reperfusion injury.

KEYWORDS:

Smac mimetics; TNF; calcium signaling; membrane pores; necroptosis

PMID:
28380356
PMCID:
PMC5465952
DOI:
10.1016/j.celrep.2017.03.024
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center