4.7 Article

Plasma membrane perforation by GSDME during apoptosis-driven secondary necrosis

期刊

出版社

SPRINGER BASEL AG
DOI: 10.1007/s00018-021-04078-0

关键词

Gasdermins; Cell death; Membrane permeabilization; Influx; Efflux; Dextrans

资金

  1. Flemish grants (EOS MODEL-IDI, FWO) [30826052]
  2. Research Foundation Flanders (FWO) [G.0E04.16N, G.0C76.18N, G.0B71.18N, G.0B96.20N, BOF16/MET_V/007, iBOF20/IBF/039 ATLANTIS, FAF-F/2016/865, F/2020/1505, F/2020/1434, 1110721N, 12S9418N]
  3. Cancer Research Institute Ghent (CRIG)
  4. Ghent Gut Inflammation Group (GGIG) consortia
  5. Flanders Institute for Biotechnology (VIB)
  6. Excellence of Science EOS MODEL-IDI (FWO) [30826052, BOF16/MET_V/007, FAF-F/2016/865]
  7. European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [648124]

向作者/读者索取更多资源

This study investigates the membrane permeabilizing features of Gasdermin E (GSDME) and its role in regulating secondary necrosis. The results show that GSDME accelerates cell lysis and affects the influx of fluorescently labeled dextrans, while the efflux is independent of GSDME expression. Furthermore, the passage of dextrans is dependent on their molecular weight.
Secondary necrosis has long been perceived as an uncontrolled process resulting in total lysis of the apoptotic cell. Recently, it was shown that progression of apoptosis to secondary necrosis is regulated by Gasdermin E (GSDME), which requires activation by caspase-3. Although the contribution of GSDME in this context has been attributed to its pore-forming capacity, little is known about the kinetics and size characteristics of this. Here we report on the membrane permeabilizing features of GSDME by monitoring the influx and efflux of dextrans of different sizes into/from anti-Fas-treated L929sAhFas cells undergoing apoptosis-driven secondary necrosis. We found that GSDME accelerates cell lysis measured by SYTOX Blue staining but does not affect the exposure of phosphatidylserine on the plasma membrane. Furthermore, loss of GSDME expression clearly hampered the influx of fluorescently labeled dextrans while the efflux happened independently of the presence or absence of GSDME expression. Importantly, both in- and efflux of dextrans were dependent on their molecular weight. Altogether, our results demonstrate that GSDME regulates the passage of compounds together with other plasma membrane destabilizing subroutines.

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