Abstract
During the progression of necroptosis and pyroptosis, the plasma membrane will become permeabilized through the activation of mixed lineage kinase domain like pseudokinase (MLKL) or gasdermin D (GSDMD), respectively. Recently, the progression of apoptotic cells into secondary necrotic cells following membrane lysis was shown to be regulated by gasdermin E (GSDME, or DFNA5), a process dependent on caspase 3-mediated cleavage of GSDME. Notably, GSDME was also proposed to negatively regulate the disassembly of apoptotic cells into smaller membrane-bound vesicles known as apoptotic bodies (ApoBDs) by promoting earlier onset of membrane permeabilisation. The presence of a process downstream of caspase 3 that would actively drive cell lysis and limit cell disassembly during apoptosis is somewhat surprising as this could favor the release of proinflammatory intracellular contents and hinder efficient clearance of apoptotic materials. In contrast to the latter studies, we present here that GSDME is not involved in regulating secondary necrosis in human T cells and monocytes, and also unlikely in epithelial cells. Furthermore, GSDME is evidently not a negative regulator of apoptotic cell disassembly in our cell models. Thus, the function of GSDME in regulating membrane permeabilization and cell disassembly during apoptosis may be more limited.
Highlights
Permeabilisation of the plasma membrane during programmed cell death is regulated by a number of distinct molecular factors
The expression of GSDME was detected in human Jurkat T cells, and induction of apoptosis by UV irradiation promoted the generation of a GSDME fragment at ∼35 kDa that corresponded to the caspase-cleaved GSDME noted in previous studies [3, 4] (Figure 1A)
We determined whether loss of GSDME will lead to a reduction in Jurkat T cells progressing to secondary necrosis upon apoptotic stimulation by monitoring the release of the cytosolic protein lactate dehydrogenase (LDH) into the culture supernatant [ used in [3, 4]]
Summary
Permeabilisation of the plasma membrane during programmed cell death is regulated by a number of distinct molecular factors. A programmed form of necrosis, plasma membrane permeabilisation is mediated through the phosphorylation and activation of MLKL (mixed lineage kinase domain like pseudokinase) by RIP3/RIP1 necrosome [1]. Plasma membrane permeabilisation during pryoptotic cell death, another form of programmed necrosis, is mediated by caspase 1/4/5 [11]-cleaved GSDMD (gasdermin D) [2]. Activation of MLKL and GSDMD can subsequently trigger their targeting toward the plasma membrane through interacting with phosphatidylinositol-4,5-bisphosphate and oligomerisation. This eventually leads to membrane permeabilisation and release of proinflammatory intracellular contents [1, 2].
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