Necroptosis Execution Is Mediated by Plasma Membrane Nanopores Independent of Calcium | Zendy

Uris Ros | Zendy; Aida PeñaBlanco | Zendy; Kay Hänggi | Zendy; Ulrich Kunzendorf | Zendy; Stefan Krautwald | Zendy; W. WeiLynn Wong | Zendy; Ana J. GarcíaSáez | Zendy

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Necroptosis Execution Is Mediated by Plasma Membrane Nanopores Independent of Calcium

Author(s) -

Uris Ros,

Aida PeñaBlanco,

Kay Hänggi,

Ulrich Kunzendorf,

Stefan Krautwald,

W. WeiLynn Wong,

Ana J. GarcíaSáez

Publication year - 2017

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2017.03.024

Subject(s) - necroptosis , microbiology and biotechnology , programmed cell death , cytosol , chemistry , tlr3 , calcium signaling , biology , signal transduction , apoptosis , biochemistry , receptor , toll like receptor , innate immune system , enzyme

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.

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