Gasdermin D pore structure reveals preferential release of mature interleukin-1

Xia, Shiyu; Zhang, Zhibin; Magupalli, Venkat Giri; Pablo, Juan Lorenzo; Dong, Ying; Vora, Setu M.; Wang, Long; Fu, Tian‐Min; Jacobson, Matthew P.; Greka, Anna; Lieberman, Judy; Ruan, Jianbin; Wu, Hao

doi:10.1038/s41586-021-03478-3

Cited by 390 publications

(403 citation statements)

References 42 publications

Supporting

Mentioning

353

Contrasting

Order By: Relevance

“…FITC-labeled dextrans are anionic while Texas Red-labeled dextrans are more neutral. Recently, the GSDMD pore was shown to be predominantly negatively charged preventing the passage of negatively charged cargos [46].…”

Section: Discussionmentioning

confidence: 99%

Gasdermin E-dependent and -independent Subroutines Regulate the Passage of Dextrans During Apoptosis-driven Secondary Necrosis.

Schutter

Ramon

Pfeuty

et al. 2021

Preprint

View full text Add to dashboard Cite

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 stimulated 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 independent of the presence or absence of GSDME expression. Importantly, both in- and efflux of dextrans was dependent on their molecular weight. Altogether, our results demonstrate that GSDME regulates the passage of compounds together with other plasma membrane destabilizing subroutines.

show abstract

Section: Discussionmentioning

confidence: 99%

Gasdermin E-dependent and -independent Subroutines Regulate the Passage of Dextrans During Apoptosis-driven Secondary Necrosis.

Schutter

Ramon

Pfeuty

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Proteolysis enables gasdermin NTD oligomerization and rapid formation of membrane pores, which have emerged as an important component of innate immune defense in mammals and primitive eukaryotes ( 7–9 ). Recent structural analyses explain a mechanism of gasdermin pore formation ( 5, 6, 10, 11 ), but the evolutionary origin and biological roles of diverse gasdermin proteins remain unknown ( 12 ).…”

Section: Main Textmentioning

confidence: 99%

“…Mammalian gasdermins assemble into membrane pores with inner diameters ranging from 135–215 Å ( 6, 10, 19 ). To compare the bGSDM pore to its mammalian counterparts, we used negative-stain EM to visualize Runella bGSDM cleavage reactions and liposome permeabilization ( Fig.…”

Section: Main Textmentioning

confidence: 99%

“…Additionally, widespread palmitoylation of bGSDMs mirrors recent results describing succination of human GSDMD and indicates that cysteine modifications are a conserved mechanism for regulating gasdermin pores ( 20 ). Release of autoinhibition triggers the assembly of gasdermin monomers into membrane pores which in mammals are customized for the transport of signaling molecules ( 10 ). In Runella , bGSDM pores assemble into webs and are much larger and more heterogeneous than the mammalian counterparts.…”

Section: Main Textmentioning

confidence: 99%

See 1 more Smart Citation

Bacterial gasdermins reveal an ancient mechanism of cell death

Johnson

Wein

Mayer

et al. 2021

Preprint

View full text Add to dashboard Cite

Gasdermin proteins form large membrane pores in human cells that release immune cytokines and induce lytic cell death. Gasdermin pore formation is triggered by caspase-mediated cleavage during inflammasome signaling and is critical for defense against pathogens and cancer. Here we discover gasdermin homologs encoded in bacteria that execute prokaryotic cell death. Structures of bacterial gasdermins reveal a conserved pore-forming domain that is stabilized in the inactive state with a buried lipid modification. We demonstrate that bacterial gasdermins are activated by dedicated caspase-like proteases that catalyze site-specific cleavage and removal of an inhibitory C-terminal peptide. Release of autoinhibition induces the assembly of >200 Å pores that form a mesh-like structure and disrupt membrane integrity. These results demonstrate that caspase-mediated activation of gasdermins is an ancient form of regulated cell death shared between bacteria and animals.

show abstract

“…IL-1β is then released from cells via the N terminal fragment of gasdermin-D, which forms oligomeric pores that traverse the lipid bilayer and rupture the cell membrane. The loss of membrane integrity by pyroptosis also leads to the release of cytosolic proteins into the extracellular milieu, such as lactate dehydrogenase enzyme (LDH), which is commonly used as an indicator of cell death [16][17][18][19][20][21]. This suicidal commitment of cells may be associated with the detection of microbial products that are sensed by cytosolic pattern recognition receptors (PRRs), such as lipopolysaccharide (LPS) detection by murine caspase-11 (caspase 4/5 in humans) [22,23].…”

Section: Nlrp3 Inflammasomes Induce Distinct Cell Fates In Phagocytesmentioning

confidence: 99%