Mechanisms of Gasdermin Recognition by Proteases

Z, Liu; Busscher, Brianna M.; Storl-Desmond, Marta; Xiao, Tsan Sam

doi:10.1016/j.jmb.2021.167274

Cited by 14 publications

(12 citation statements)

References 76 publications

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“…Gasdermin-D can be activated by a variety of caspases including caspase-1, caspase-4, and caspase-8 in humans, or caspase-11 in mice (40,41,43,59). Similar to our findings, another study showed that LPS plus Shiga toxin 2 promoted caspase-dependent gasdermin-D activation that was independent of NLRP3 (60).…”

Section: Discussionsupporting

confidence: 89%

Regulation of Synovial γδ T Cell Ligand Expression by Mitochondrial Reactive Oxygen Species and Gasdermin-D

Collins

Hahn

Jiang

et al. 2023

The Journal of Immunology

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γδ T cells reside at mucosal and epithelial barriers, and they often accumulate at sites of inflammation, both infectious and autoimmune, as well as in certain tumors. However, progress in understanding their function is considerably hampered by a lack of full understanding of the ligands recognized by TCR-γδ and how expression of these ligands is regulated. We recently developed a soluble human TCR-γδ (Vγ9Vδ1) tetramer from a synovial γδ T cell clone of a Lyme arthritis patient and observed that it stains monocytes activated by Borrelia burgdorferi. Those findings are extended in the current study to further examine the physiological regulation of ligand expression on monocytes. The TCR-γδ ligand is induced by a variety of TLR agonists and requires NF-κB activation. Of particular interest is that ligand expression also requires caspase activation of the inflammasome and is dependent on active metabolism, mitochondrial reactive oxygen species, and activation of gasdermin-D. Consistent with these observations, the TCR-γδ ligand is expressed by a subset of metabolically active CD14+CD16+ monocytes and colocalizes intracellularly with mitochondria. The findings suggest a model in which synovial γδ T cell ligand is a self-antigen whose surface expression is increased by inflammatory conditions and mitochondrial stress.

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Section: Discussionsupporting

confidence: 89%

Regulation of Synovial γδ T Cell Ligand Expression by Mitochondrial Reactive Oxygen Species and Gasdermin-D

Collins

Hahn

Jiang

et al. 2023

The Journal of Immunology

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“…However, only Gsdma1 and Gsdma3 are present in skin with Gsdma1 possessing the conserved SpeB cleavage site of human GSDMA. 5 Detailed analysis of Gsdma1 -deficient mice confirmed that GSDMA is relevant for the pyroptolytic response of epithelial cells to SpeB and even crucial for GAS-immunity of the host. This was demonstrated by the observation that knockout animals did not develop dermonecrotic skin lesions, but showed more severe systemic disseminating infections with increased bacterial loads in liver and spleen, which correlated with significantly increased mortality.…”

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confidence: 90%

“…In contrast to the N- and C-terminal highly conserved regions, the linker region is quite variable in sequence and length among gasdermin family members. 5 This seems to be important for the activation of specific gasdermins and their regulation by different cysteine and serine proteases when ensuring cell death mechanisms due to diverse pathological stimuli. For GSDMA, unlike all other gasdermins, no eukaryotic proteases have yet been characterized, 5 therefore making the screening for potential effectors particularly interesting.…”

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confidence: 99%

“… 5 This seems to be important for the activation of specific gasdermins and their regulation by different cysteine and serine proteases when ensuring cell death mechanisms due to diverse pathological stimuli. For GSDMA, unlike all other gasdermins, no eukaryotic proteases have yet been characterized, 5 therefore making the screening for potential effectors particularly interesting. Deng et al postulate that the virulence factor SpeB can directly cleave GSDMA.…”

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confidence: 99%

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Suicide signaling by GSDMA: a single-molecule mechanism for recognition and defense against SpeB-expressing GAS

Symmank

Jacobs

Schulze‐Späte

2022

Sig Transduct Target Ther

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“…However, with this discovery and the classification of pyroptosis being a gasdermin-driven cell death [ 27 , 28 ], pyroptotic killing is no longer limited to inflammasome signaling. GSDMD and other gasdermin family members incorporating GSDMA, GSDMB, GSDMC and GSDME, can be processed independent of inflammasome complexes, by both cell death associated caspases and other proteases, such as granzymes, to form plasma membrane pores and trigger pyroptotic cell death [ 29 ]. These gasdermins are generally composed of a N-terminal pore-forming domain, though the gasdermin family member Pejvakin (PJVK) is an exception to this, an interdomain linker that is cleaved to unleash gasdermin activity, and an autoinhibitory C-terminal domain.…”

Section: Introductionmentioning

confidence: 99%

No longer married to inflammasome signaling: the diverse interacting pathways leading to pyroptotic cell death

Weir

Vince

2022

Biochemical Journal

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For over 15 years the lytic cell death termed pyroptosis was defined by its dependency on the inflammatory caspase, caspase-1, which, upon pathogen sensing, is activated by innate immune cytoplasmic protein complexes known as inflammasomes. However, this definition of pyroptosis changed when the pore-forming protein gasdermin D (GSDMD) was identified as the caspase-1 (and caspase-11) substrate required to mediate pyroptotic cell death. Consequently, pyroptosis has been redefined as a gasdermin-dependent cell death. Studies now show that, upon liberation of the N-terminal domain, five gasdermin family members, GSDMA, GSDMB, GSDMC, GSDMD and GSDME can all form plasma membrane pores to induce pyroptosis. Here, we review recent research into the diverse stimuli and cell death signaling pathways involved in the activation of gasdermins; death and toll-like receptor triggered caspase-8 activation of GSDMD or GSMDC, apoptotic caspase-3 activation of GSDME, perforin-granzyme A activation of GSDMB, and bacterial protease activation of GSDMA. We highlight findings that have begun to unravel the physiological situations and disease states that result from gasdermin signaling downstream of inflammasome activation, death receptor and mitochondrial apoptosis, and necroptosis. This new era in cell death research therefore holds significant promise in identifying how distinct, yet often networked, pyroptotic cell death pathways might be manipulated for therapeutic benefit to treat a range of malignant conditions associated with inflammation, infection and cancer.

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Mechanisms of Gasdermin Recognition by Proteases

Cited by 14 publications

References 76 publications

Regulation of Synovial γδ T Cell Ligand Expression by Mitochondrial Reactive Oxygen Species and Gasdermin-D

Regulation of Synovial γδ T Cell Ligand Expression by Mitochondrial Reactive Oxygen Species and Gasdermin-D

Suicide signaling by GSDMA: a single-molecule mechanism for recognition and defense against SpeB-expressing GAS

No longer married to inflammasome signaling: the diverse interacting pathways leading to pyroptotic cell death

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