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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

Regulatory roles of Gsdma3/GSDMA in autophagy or apoptosis. (a) Gsdma3 acts as a key mediator in the TNF-α-induced apoptosis pathway. TNF-α can upregulate Gsdma3, whereas Gsdma3 causes the catagen-associated apoptosis of hair follicle keratinocytes by directly enhancing the caspase-3 expression. (b) Gsdma3 causes autophagy through a mitochondria-dependent pathway. Mutant Gsdma3 loses its whole C-terminal domain, consequently releasing the intrinsic pro-autophagic activity of the N-terminal domain. Then, the unmasked N-terminal domain of Gsdma3 is associated with Hsp90 to be delivered to mitochondria through mitochondrial importer receptor Tom70, where it interacts with the mitochondrial chaperone Trap1 and induces mitochondrial permeability transition (MPT) pore opening, mitochondrial reactive oxygen species (ROS) production, cytochrome c releasing, resulting finally in cell death. (c) Human GSDMA involves transforming growth factor (TGF)-β-induced apoptosis. TGF-β upregulates GSDMA expression by LIM domain only 1 (LMO1) induction through a sequence to which LMO1 binds, in a GSDMA promoter region. Ultimately, the increased GSDMA induces apoptosis of the pit cells of human gastric epithelium
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fig2: Regulatory roles of Gsdma3/GSDMA in autophagy or apoptosis. (a) Gsdma3 acts as a key mediator in the TNF-α-induced apoptosis pathway. TNF-α can upregulate Gsdma3, whereas Gsdma3 causes the catagen-associated apoptosis of hair follicle keratinocytes by directly enhancing the caspase-3 expression. (b) Gsdma3 causes autophagy through a mitochondria-dependent pathway. Mutant Gsdma3 loses its whole C-terminal domain, consequently releasing the intrinsic pro-autophagic activity of the N-terminal domain. Then, the unmasked N-terminal domain of Gsdma3 is associated with Hsp90 to be delivered to mitochondria through mitochondrial importer receptor Tom70, where it interacts with the mitochondrial chaperone Trap1 and induces mitochondrial permeability transition (MPT) pore opening, mitochondrial reactive oxygen species (ROS) production, cytochrome c releasing, resulting finally in cell death. (c) Human GSDMA involves transforming growth factor (TGF)-β-induced apoptosis. TGF-β upregulates GSDMA expression by LIM domain only 1 (LMO1) induction through a sequence to which LMO1 binds, in a GSDMA promoter region. Ultimately, the increased GSDMA induces apoptosis of the pit cells of human gastric epithelium

Mentions: Previous reports suggest that Gsdma3 is associated with tumor necrosis factor TNF-α-induced apoptosis.18, 27, 28 In morphology, Lei et al.29 showed that Gsdma3 gene mutation gave rise to abnormal catagen with unshortened length and unshrunk structure of the hair follicle so that the development of catagen phase was inhibited. By testing the expression of caspase-3, it was confirmed that the Gsdma3 gene mutation suppressed the catagen-associated apoptosis of hair follicle keratinocytes. In 2012, further study demonstrated that Gsdma3 was a key mediator in the TNF-α-induced apoptosis pathway.28 After in vivo TNF-α induction, Gsdma3 expression was significantly augmented in keratinocytes, suggesting that TNF-α acts as a new mediator of Gsdma3 expression. As a result, Gsdma3 causes the catagen-associated apoptosis of hair follicle keratinocytes by directly enhancing the caspase-3 expression (Figure 2a).


‘ Hints' in the killer protein gasdermin D: unveiling the secrets of gasdermins driving cell death
Regulatory roles of Gsdma3/GSDMA in autophagy or apoptosis. (a) Gsdma3 acts as a key mediator in the TNF-α-induced apoptosis pathway. TNF-α can upregulate Gsdma3, whereas Gsdma3 causes the catagen-associated apoptosis of hair follicle keratinocytes by directly enhancing the caspase-3 expression. (b) Gsdma3 causes autophagy through a mitochondria-dependent pathway. Mutant Gsdma3 loses its whole C-terminal domain, consequently releasing the intrinsic pro-autophagic activity of the N-terminal domain. Then, the unmasked N-terminal domain of Gsdma3 is associated with Hsp90 to be delivered to mitochondria through mitochondrial importer receptor Tom70, where it interacts with the mitochondrial chaperone Trap1 and induces mitochondrial permeability transition (MPT) pore opening, mitochondrial reactive oxygen species (ROS) production, cytochrome c releasing, resulting finally in cell death. (c) Human GSDMA involves transforming growth factor (TGF)-β-induced apoptosis. TGF-β upregulates GSDMA expression by LIM domain only 1 (LMO1) induction through a sequence to which LMO1 binds, in a GSDMA promoter region. Ultimately, the increased GSDMA induces apoptosis of the pit cells of human gastric epithelium
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384029&req=5

fig2: Regulatory roles of Gsdma3/GSDMA in autophagy or apoptosis. (a) Gsdma3 acts as a key mediator in the TNF-α-induced apoptosis pathway. TNF-α can upregulate Gsdma3, whereas Gsdma3 causes the catagen-associated apoptosis of hair follicle keratinocytes by directly enhancing the caspase-3 expression. (b) Gsdma3 causes autophagy through a mitochondria-dependent pathway. Mutant Gsdma3 loses its whole C-terminal domain, consequently releasing the intrinsic pro-autophagic activity of the N-terminal domain. Then, the unmasked N-terminal domain of Gsdma3 is associated with Hsp90 to be delivered to mitochondria through mitochondrial importer receptor Tom70, where it interacts with the mitochondrial chaperone Trap1 and induces mitochondrial permeability transition (MPT) pore opening, mitochondrial reactive oxygen species (ROS) production, cytochrome c releasing, resulting finally in cell death. (c) Human GSDMA involves transforming growth factor (TGF)-β-induced apoptosis. TGF-β upregulates GSDMA expression by LIM domain only 1 (LMO1) induction through a sequence to which LMO1 binds, in a GSDMA promoter region. Ultimately, the increased GSDMA induces apoptosis of the pit cells of human gastric epithelium
Mentions: Previous reports suggest that Gsdma3 is associated with tumor necrosis factor TNF-α-induced apoptosis.18, 27, 28 In morphology, Lei et al.29 showed that Gsdma3 gene mutation gave rise to abnormal catagen with unshortened length and unshrunk structure of the hair follicle so that the development of catagen phase was inhibited. By testing the expression of caspase-3, it was confirmed that the Gsdma3 gene mutation suppressed the catagen-associated apoptosis of hair follicle keratinocytes. In 2012, further study demonstrated that Gsdma3 was a key mediator in the TNF-α-induced apoptosis pathway.28 After in vivo TNF-α induction, Gsdma3 expression was significantly augmented in keratinocytes, suggesting that TNF-α acts as a new mediator of Gsdma3 expression. As a result, Gsdma3 causes the catagen-associated apoptosis of hair follicle keratinocytes by directly enhancing the caspase-3 expression (Figure 2a).

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