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ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation

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Science  23 Nov 2018:
Vol. 362, Issue 6417, pp. 956-960
DOI: 10.1126/science.aar7607

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Fine-tuning pyroptosis with ESCRT-III

Pyroptosis is an inflammatory form of cell death induced by select caspases downstream of inflammasome complexes. These caspases cleave gasdermin D (GSDMD), whose N-terminal fragments quickly form large permeability pores that induce cell death. However, a large percentage of cells with active inflammasomes are resistant to pyroptosis. Rühl et al. found that the membrane-remodeling ESCRT-III machinery was recruited to the plasma membrane upon GSDMD activation. ESCRT-III–dependent membrane repair limited proinflammatory cytokine secretion and pyroptosis after activation of inflammasomes.

Science, this issue p. 956

Abstract

Pyroptosis is a lytic form of cell death that is induced by inflammatory caspases upon activation of the canonical or noncanonical inflammasome pathways. These caspases cleave gasdermin D (GSDMD) to generate an N-terminal GSDMD fragment, which executes pyroptosis by forming membrane pores. We found that calcium influx through GSDMD pores serves as a signal for cells to initiate membrane repair by recruiting the endosomal sorting complexes required for transport (ESCRT) machinery to damaged membrane areas, such as the plasma membrane. Inhibition of the ESCRT-III machinery strongly enhances pyroptosis and interleukin-1β release in both human and murine cells after canonical or noncanonical inflammasome activation. These results not only attribute an anti-inflammatory role to membrane repair by the ESCRT-III system but also provide insight into general cellular survival mechanisms during pyroptosis.

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