Contribution of TMEM16F to pyroptotic cell death

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.

TMEM16F Aggravates Neuronal Loss by Mediating Microglial Phagocytosis of Neurons in a Rat Experimental Cerebral Ischemia and Reperfusion Model

“…It has been reported that expression of TMEM16F is significantly higher in macrophages, where it supports phagocytic activity and cell death (57). Recent studies find that TMEM16F plays an important role in regulating spinal microglia function in neuropathic pain states (58) and spinal cord injury (59).…”

Contribution of Anoctamins to Cell Survival and Cell Death

“…Meanwhile, a number of independent regulated cell death pathways have been identified [245]. Initially, ANO6 has been reported in the context of apoptosis, but is now shown to be activated also during necroptosis, pyroptosis and ferroptosis [95,199,246,247,248]. Thus, activation of anoctamins, particularly of ANO6, might be a possibility to induce cell death in cancer cells.…”

Flavonoids: Broad Spectrum Agents on Chronic Inflammation

“…Recently, besides canonical inflammasome pathways, the importance of noncanonical pathways has been emerged in inflammasome activation accompanied by components such as caspase-8, -11, and P2X7 receptor (P2X7R) (Kayagaki et al ., 2011; Gurung et al ., 2014; Ousingsawat et al ., 2018). It has been shown that apigenin supplementation can inhibit both caspase-1 and caspase-11 in chronic ulcerative colitis model (Márquez-Flores et al ., 2016).…”