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‘ Hints' in the killer protein gasdermin D: unveiling the secrets of gasdermins driving cell death

View Article: PubMed Central - PubMed

ABSTRACT

Pyroptosis is a lytic form of cell death distinguished from apoptosis, ferroptosis, necrosis, necroptosis, NETosis, oncosis, pyronecrosis and autophagy. Proinflammatory caspases cleave a gasdermin D (GSDMD) protein to generate a 31 kDa N-terminal domain. The cleavage relieves the intramolecular inhibition on the gasdermin-N domain, which then moves to the plasma membrane to exhibit pore-forming activity. Thus, GSDMD acts as the final and direct executor of pyroptotic cell death. Owing to the selective targeting of the inner leaflet of the plasma membrane with the pore-forming that determines pyroptotic cell death, GSDMD could be a potential target to control cell death or extracellular bacterial infections. Intriguingly, other gasdermin family members also share similar N-terminal domains, but they present different cell death programs. Herein, we summarize features and functions of the novel player proteins in cell death, including GSDMD triggering pyroptosis, Gsdma3/GSDMA initiating autophagy/apoptosis and DFNA5 inducing apoptosis/secondary necrosis. The gasdermin N terminus appears to be a novel pore-forming protein. This provides novel insight into the underlying roles and mechanisms of lytic or nonlytic forms of programmed cell death, as well as their potential applications in inflammation-associated diseases.

No MeSH data available.


Related in: MedlinePlus

Potential mechanistic process of apoptosis/secondary necrosis mediated by DFNA5. Intrinsic apoptosis is initiated by various death stimuli. They lead to permeabilization of the outer mitochondrial membrane, causing the release of cytochrome c. The latter binds to Apaf-1, followed successively by apoptosome formation, procaspase-9 recruitment/activation and activation of procaspase-3. Caspase-3 can also be activated by extrinsic or receptor-mediated apoptosis, and directly by active caspase-8. DFNA5 consists of two globular domains. The N-terminal domain of the apoptosis-inducing region located in exon 2 and exon 6 displays a proapoptotic activity, whereas the C-terminal domain, including exon 8, may serve as a regulator that folds back to mask the apoptosis-inducing N-terminal domain. Mutant DFNA5 skipping of exon 8 can change and shortens its C-terminal domain, thereby releasing the autoinhibition activity of the C-terminal domain with the activation of the N-terminal function. In other respect, active caspase-3 also can cleave DFNA5 to generate active DFNA5-N terminal that targets the plasma membrane and permeabilizes it by forming DFNA5 pores to induce secondary necrosis cell death, ultimately leading to HL
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fig3: Potential mechanistic process of apoptosis/secondary necrosis mediated by DFNA5. Intrinsic apoptosis is initiated by various death stimuli. They lead to permeabilization of the outer mitochondrial membrane, causing the release of cytochrome c. The latter binds to Apaf-1, followed successively by apoptosome formation, procaspase-9 recruitment/activation and activation of procaspase-3. Caspase-3 can also be activated by extrinsic or receptor-mediated apoptosis, and directly by active caspase-8. DFNA5 consists of two globular domains. The N-terminal domain of the apoptosis-inducing region located in exon 2 and exon 6 displays a proapoptotic activity, whereas the C-terminal domain, including exon 8, may serve as a regulator that folds back to mask the apoptosis-inducing N-terminal domain. Mutant DFNA5 skipping of exon 8 can change and shortens its C-terminal domain, thereby releasing the autoinhibition activity of the C-terminal domain with the activation of the N-terminal function. In other respect, active caspase-3 also can cleave DFNA5 to generate active DFNA5-N terminal that targets the plasma membrane and permeabilizes it by forming DFNA5 pores to induce secondary necrosis cell death, ultimately leading to HL

Mentions: Transfecting the cell death-causing DFNA5 mutant into yeast48 or mammalian cells49 showed a toxic effect of the mutant protein, which was not coming after the transfection of its wild-type. Other transfection studies in mammalian cell lines have further strengthened the evidence, that is, the critical role of DFNA5 in apoptotic pathways.50 The transfection of its mutant resulted in cell death, whereas the transfection of its WT did not. This effect was observed not only in human cell lines, including HEK293T, COS7, MCF7, and HELA cells, but also in the yeast model Saccharomyces cerevisiae.51 Morphological analysis in combination with fluorescent labeling identified apoptosis as the cause of the observed cell death.50 Interestingly, the apoptosis-inducing domain is shared by WT and mutant DFNA5, leading to a hypothesis that the apoptotic induction is an intrinsic feature of DFNA5. Further experimental evidence for this hypothesis was provided by hydrophobic cluster analysis of DFNA5, revealing that it contains two globular domains connected by a hinge region. The N-terminal domain located in exon 2 and exon 6 displays a proapoptotic activity, whereas the C-terminal domain consisting of the amino acid residues 282–496 (exon 8 included) may fold back to mask the apoptosis-inducing function of the N-terminal domain (Figure 3). Using the yeast system and human HEK293T cells further confirms that the N-terminal but not the C-terminal domain leads to the apoptotic cell death. On the basis of the crystal structure of Gsdma3, we can find that the residues in gasdermin-C that make the hydrophobic core largely determining the autoinhibition are highly conserved in the gasdermin family (Table 1). Interestingly, all DFNA5 mutations which skip exon 8 are devoid of the critical residues (I313, F388 and A392) that make the hydrophobic core of DFNA5 (Table 1). Thus, the mutation of DFNA5 releases the autoinhibition activity of the C-terminal domain, resulting in the activation of the N-terminal function (Figure 3). Given that PJVK shows a high N-terminal similarity to DFNA5, it was used to test whether the transfection of the N-terminal is also responsible for apoptotic cell death, but it was not the case.50 Therefore, the apoptosis-inducing role may be specific for DFNA5.


‘ Hints' in the killer protein gasdermin D: unveiling the secrets of gasdermins driving cell death
Potential mechanistic process of apoptosis/secondary necrosis mediated by DFNA5. Intrinsic apoptosis is initiated by various death stimuli. They lead to permeabilization of the outer mitochondrial membrane, causing the release of cytochrome c. The latter binds to Apaf-1, followed successively by apoptosome formation, procaspase-9 recruitment/activation and activation of procaspase-3. Caspase-3 can also be activated by extrinsic or receptor-mediated apoptosis, and directly by active caspase-8. DFNA5 consists of two globular domains. The N-terminal domain of the apoptosis-inducing region located in exon 2 and exon 6 displays a proapoptotic activity, whereas the C-terminal domain, including exon 8, may serve as a regulator that folds back to mask the apoptosis-inducing N-terminal domain. Mutant DFNA5 skipping of exon 8 can change and shortens its C-terminal domain, thereby releasing the autoinhibition activity of the C-terminal domain with the activation of the N-terminal function. In other respect, active caspase-3 also can cleave DFNA5 to generate active DFNA5-N terminal that targets the plasma membrane and permeabilizes it by forming DFNA5 pores to induce secondary necrosis cell death, ultimately leading to HL
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5384029&req=5

fig3: Potential mechanistic process of apoptosis/secondary necrosis mediated by DFNA5. Intrinsic apoptosis is initiated by various death stimuli. They lead to permeabilization of the outer mitochondrial membrane, causing the release of cytochrome c. The latter binds to Apaf-1, followed successively by apoptosome formation, procaspase-9 recruitment/activation and activation of procaspase-3. Caspase-3 can also be activated by extrinsic or receptor-mediated apoptosis, and directly by active caspase-8. DFNA5 consists of two globular domains. The N-terminal domain of the apoptosis-inducing region located in exon 2 and exon 6 displays a proapoptotic activity, whereas the C-terminal domain, including exon 8, may serve as a regulator that folds back to mask the apoptosis-inducing N-terminal domain. Mutant DFNA5 skipping of exon 8 can change and shortens its C-terminal domain, thereby releasing the autoinhibition activity of the C-terminal domain with the activation of the N-terminal function. In other respect, active caspase-3 also can cleave DFNA5 to generate active DFNA5-N terminal that targets the plasma membrane and permeabilizes it by forming DFNA5 pores to induce secondary necrosis cell death, ultimately leading to HL
Mentions: Transfecting the cell death-causing DFNA5 mutant into yeast48 or mammalian cells49 showed a toxic effect of the mutant protein, which was not coming after the transfection of its wild-type. Other transfection studies in mammalian cell lines have further strengthened the evidence, that is, the critical role of DFNA5 in apoptotic pathways.50 The transfection of its mutant resulted in cell death, whereas the transfection of its WT did not. This effect was observed not only in human cell lines, including HEK293T, COS7, MCF7, and HELA cells, but also in the yeast model Saccharomyces cerevisiae.51 Morphological analysis in combination with fluorescent labeling identified apoptosis as the cause of the observed cell death.50 Interestingly, the apoptosis-inducing domain is shared by WT and mutant DFNA5, leading to a hypothesis that the apoptotic induction is an intrinsic feature of DFNA5. Further experimental evidence for this hypothesis was provided by hydrophobic cluster analysis of DFNA5, revealing that it contains two globular domains connected by a hinge region. The N-terminal domain located in exon 2 and exon 6 displays a proapoptotic activity, whereas the C-terminal domain consisting of the amino acid residues 282–496 (exon 8 included) may fold back to mask the apoptosis-inducing function of the N-terminal domain (Figure 3). Using the yeast system and human HEK293T cells further confirms that the N-terminal but not the C-terminal domain leads to the apoptotic cell death. On the basis of the crystal structure of Gsdma3, we can find that the residues in gasdermin-C that make the hydrophobic core largely determining the autoinhibition are highly conserved in the gasdermin family (Table 1). Interestingly, all DFNA5 mutations which skip exon 8 are devoid of the critical residues (I313, F388 and A392) that make the hydrophobic core of DFNA5 (Table 1). Thus, the mutation of DFNA5 releases the autoinhibition activity of the C-terminal domain, resulting in the activation of the N-terminal function (Figure 3). Given that PJVK shows a high N-terminal similarity to DFNA5, it was used to test whether the transfection of the N-terminal is also responsible for apoptotic cell death, but it was not the case.50 Therefore, the apoptosis-inducing role may be specific for DFNA5.

View Article: PubMed Central - PubMed

ABSTRACT

Pyroptosis is a lytic form of cell death distinguished from apoptosis, ferroptosis, necrosis, necroptosis, NETosis, oncosis, pyronecrosis and autophagy. Proinflammatory caspases cleave a gasdermin D (GSDMD) protein to generate a 31 kDa N-terminal domain. The cleavage relieves the intramolecular inhibition on the gasdermin-N domain, which then moves to the plasma membrane to exhibit pore-forming activity. Thus, GSDMD acts as the final and direct executor of pyroptotic cell death. Owing to the selective targeting of the inner leaflet of the plasma membrane with the pore-forming that determines pyroptotic cell death, GSDMD could be a potential target to control cell death or extracellular bacterial infections. Intriguingly, other gasdermin family members also share similar N-terminal domains, but they present different cell death programs. Herein, we summarize features and functions of the novel player proteins in cell death, including GSDMD triggering pyroptosis, Gsdma3/GSDMA initiating autophagy/apoptosis and DFNA5 inducing apoptosis/secondary necrosis. The gasdermin N terminus appears to be a novel pore-forming protein. This provides novel insight into the underlying roles and mechanisms of lytic or nonlytic forms of programmed cell death, as well as their potential applications in inflammation-associated diseases.

No MeSH data available.


Related in: MedlinePlus