Abstract
Pyroptosis is a highly inflammatory form of programmed cell death that is caused by infection with intracellular pathogens and activation of canonical or noncanonical inflammasomes. The purinergic receptor P2X7 is activated by the noncanonical inflammasome and contributes essentially to pyroptotic cell death. The Ca2+ activated phospholipid scramblase and ion channel TMEM16F has been shown earlier to control cellular effects downstream of purinergic P2X7 receptors that ultimately lead to cell death. As pyroptotic cell death is accompanied by an increases in intracellular Ca2+, we asked whether TMEM16F is activated during pyroptosis. The N-terminal cleavage product of gasdermin D (GD-N) is an executioner of pyroptosis by forming large plasma membrane pores. Expression of GD-N enhanced basal Ca2+ levels and induced cell death. We observed that GD-N induced cell death in HEK293 and HAP1 cells, which was depending on expression of endogenous TMEM16F. GD-N activated large whole cell currents that were suppressed by knockdown or inhibition of TMEM16F. The results suggest that whole cell currents induced by the pore forming domain of gasdermin-D, are at least in part due to activation of TMEM16F. Knockdown of other TMEM16 paralogues expressed in HAP1 cells suggest TMEM16F as a crucial element during pyroptosis and excluded a role of other TMEM16 proteins. Thus TMEM16F supports pyroptosis and other forms of inflammatory cell death such as ferroptosis. Its potent inhibition by tannic acid may be part of the anti-inflammatory effects of flavonoids.
Highlights
Introduction IntracellularCa2+ is enhanced during many biological processes including inflammation
When gasdermin D (GD-N)-transfected cells were grown in the presence of the TMEM16F-inhibitor tannic acid (TA), the cell death-inducing effect of GD-N was completely abolished, suggesting that TMEM16F contributes to GD-N induced cell death
While GD was found to be distributed homogenously throughout the cytosol, GD-N was localized as spots in the plasma membrane (Fig. 1e)
Summary
Introduction IntracellularCa2+ is enhanced during many biological processes including inflammation. Large gasdermin D pores are regarded as effectors of pyroptosis. These pores may lead to an increase in intracellular Ca2+ by permeabilizing the plasma membrane and prob-. Noncanonical large supramolecular complex that activates caspase-1 inflammasomes lead to caspase-11-dependent pyroptosis during pyroptosis. Pyroptosis, a highly inflammatory form due to activation of pannexin-1, release of ATP binding to of programmed cell death, occurs upon infection with purinergic P2X7 receptors and consecutively increases intracellular pathogens and is part of the antimicrobial intracellular Ca2+ 5. Pyroptotic cell death lipid scramblase and ion channel TMEM16F has been results in plasma membrane (PM) rupture and release of so called damage-associated molecular pattern (DAMP) molecules[1].
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