Inflammasome - activated gasdermin D causes pyroptosis by forming membrane pores

By Xing Liu, Zhibin Zhang, J. Ruan, Youdong Pan, V. Magupalli, Hao Wu, J. Lieberman. Nature, 2016

2,848 citations recorded by the source corpus.

Inflammatory caspases (caspases 1, 4, 5 and 11) are activated in response to microbial infection and danger signals. When activated, they cleave mouse and human gasdermin D (GSDMD) after Asp276 and Asp275, respectively, to generate an N-terminal cleavage product (GSDMD-NT) that triggers inflammatory death (pyroptosis) and release of inflammatory cytokines such as interleukin-1β. Cleavage removes the C-terminal fragment (GSDMD-CT), which is thought to fold back on GSDMD-NT to inhibit its activation. However, how GSDMD-NT causes cell death is unknown. Here we show that GSDMD-NT oligomerizes in membranes to form pores that are visible by electron microscopy. GSDMD-NT binds to phosphatidylinositol phosphates and phosphatidylserine (restricted to the cell membrane inner leaflet) and cardiolipin (present in the inner and outer leaflets of bacterial membranes). Mutation of four evolutionarily conserved basic residues blocks GSDMD-NT oligomerization, membrane binding, pore formation and pyroptosis. Because of its lipid-binding preferences, GSDMD-NT kills from within the cell, but does not harm neighbouring mammalian cells when it is released during pyroptosis. GSDMD-NT also kills cell-free bacteria in vitro and may have a direct bactericidal effect within the cytosol of host cells, but the importance of direct bacterial killing in controlling in vivo infection remains to be determined.

Subfields: Hematology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/67ca998955c994e7a33cedceca3d2fb521e51094

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Hematology

In Molecular Biology

In Physiology

Citations in the corpus

Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death. (2017, background): “Moreover, it has also been proposed that activated GSDMD may form pores on bacterial membranes to kill the intracellular bacteria [36], but it remains to be determined how GSDMD protein could pass through the thick cell wall to gain access to bacterial inner membrane.”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “Cleaved GSDMD-N acquires the ability to translocate to the inner leaflet of the plasma membrane (or the bacterial plasma membrane), where it binds with high specificity to selected phosphoinositides (or cardiolipin) [629, 630].”
Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions (2020, neutral): “Caspase-1 cleaves and activates IL-1β and IL-18, and induces a hyperinflammatory form of cell death, termed pyroptosis, through the cleavage of the pore-forming gasdermin-D [32,35].”
The pore forming protein gasdermin D regulates interleukin-1 secretion from living macrophages (2017, neutral): “Upon cleavage, the N-terminal fragment of GSDMD oligomerizes into ring-shaped structures in membranes (Aglietti et al., 2016; Ding et al., 2016; Liu et al., 2016; Sborgi et al., 2016).”
Pattern Recognition Receptors and the Host Cell Death Molecular Machinery (2018, background): “Extracellular bacteria can also be controlled by the action of antimicrobial peptides (160, 161) and potentially by the GSDMD Nterminal domain released during cell lysis due to its affinity to cardiolipin and phosphatidylserine expressed in some bacterial cell membranes, such as Escherichia coli and”
Gasdermins: Effectors of pyroptosis (2017, background): “Gasdermin D does not bind the non-charged head group lipid phosphatidylinositol (PI) or the positively charged head group lipids phosphatidylcholine (PC) and phosphatidylethanolamine (PE)[15,18].”