Mechanism and Regulation of Gasdermin-Mediated Cell Death

Xia, Shiyu; Hollingsworth, Louis; Wu, Hao

doi:10.1101/cshperspect.a036400

Cited by 116 publications

(90 citation statements)

References 86 publications

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“…GSDME has been proposed as a tumor suppressor, and is now believed to be a strategy to boost the immunogenicity of cancer cell death. 30,31 Our results demonstrated that GSDME knockdown prevented secondary necrosis and fibrogenesis in diabetic tubular cells. Our work brings about an advance in identifying GSDME as a promising target for the treatment of DKD.…”

Section: Discussionmentioning

confidence: 57%

<p>Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis</p>

Su¹,

Wang²,

Zhang³

et al. 2020

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These authors contributed equally to this workBackground: Apoptosis has been repeatedly linked with diabetic kidney disease (DKD), which is a programmed cell death mediated by effector caspases-3, 6 and 7, targeting >600 substrates. However, the pathophysiologic correlations of this process remain obscure. As a putative tumor suppressor, gasdermin E (GSDME) was recently reported to be cleaved by caspase-3 to produce a GSDME-N fragment which targets the plasma membrane to switch apoptosis to secondary necrosis. However, it remains elusive whether GSDME is involved in the regulation of DKD. Methods: To evaluate the therapeutic potential of caspase-3 inhibition in DKD, we administered caspase-3 inhibitor Z-DEVD-FMK to STZ-induced diabetic mice for eight weeks. Albuminuria, renal function, pathological changes, and indicators of secondary necrosis and fibrosis were evaluated. In vitro, human tubule epithelial cells (HK-2 cells) were subjected to high-glucose treatment. Secondary necrosis was determined by LDH release, GSDME cleavage, and morphological feature under confocal microscopy. Z-DEVD-FMK and GSDME inhibition by shRNA were administered to suppress the cleavage and expression of GSDME. Flow cytometry, cytotoxicity assay and immunoblot were used to assess cell death and fibrogenesis. Results: Caspase-3 inhibition by Z-DEVD-FMK ameliorated albuminuria, renal function, and tubulointerstitial fibrosis in diabetic mice. The nephroprotection mediated by Z-DEVD-FMK was potentially associated with inhibition of GSDME. In vitro, molecular and morphological features of secondary necrosis were observed in glucose-stressed HK-2 cells, evidenced by active GSDME cleavage, ballooning of the cell membrane, and release of cellular contents. Here we showed that caspase-3 inhibition prevented GSDME activation and cell death in glucose-treated tubular cells. Specifically, knocking down GSDME directly inhibited secondary necrosis and fibrogenesis. Conclusion: These data suggest GSDME-dependent secondary necrosis plays a crucial role in renal injury, and provides a new insight into the pathogenesis of DKD and a promising target for its treatment.

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Section: Discussionmentioning

confidence: 57%

<p>Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis</p>

Su¹,

Wang²,

Zhang³

et al. 2020

DMSO

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“…This process is thought to promote the extracellular release of nuclear HMGB1 during infections (Lamkanfi et al, 2010). While the secretion of lactate dehydrogenase (LDH), HMGB1, and IL-1β occurs without rupture, HMGB1 can be released to the extracellular matrix via passive diffusion through Gasdermin D pores (Davis et al, 2019;Miao et al, 2019), and living cells are capable of releasing inflammasome related cytokines via the Gasdermin D pore without the development of pyroptosis (Xia et al, 2019). Another novel finding is that GPX4 deficiency increases lipid peroxidation, thus exacerbating GSDMD-mediated pyroptosis in macrophages as well as septic lethality in mice.…”

Section: Discussionmentioning

confidence: 99%

Contribution of TGF-Beta-Mediated NLRP3-HMGB1 Activation to Tubulointerstitial Fibrosis in Rat With Angiotensin II-Induced Chronic Kidney Disease

Zhang

Fan

Cai

et al. 2020

Front. Cell Dev. Biol.

168

130

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Fibrosis is a common phenotype that often leads to the progression of blood pressure-induced chronic kidney disease (CKD). TGF-beta plays an important role in promoting pathogenesis, and NLRP3 is a critical mediator in the progression of blood pressure-induced CKD. However, the pathophysiological roles of the TGF-betamediated NLRP3 pathway in modulating fibrosis in blood pressure-induced CKD have not been elucidated. The present study aims to investigate the contribution of TGFbeta-mediated NLRP3 inflammasome to renal fibrosis in rats with high blood pressure. By treating rats with angiotensin II (Ang II) for 14 days, we observed the development of fibrosis, characterized by epithelial-mesenchymal transition (EMT) markers [alphasmooth muscle actin (alpha-SMA), MMP-2, and MMP-9]. Immunohistochemical analysis further revealed that TGF-beta and NLRP3 inflammasome activation [high-mobility group box 1 (HMGB1), IL-1beta, and NLRP3] were significantly upregulated in the kidney of rats with Ang II-induced hypertension. Interestingly, we observed that Ang II could not increase the production of NLRP3 proteins, but TGF-beta could induce NLRP3 protein expression in cultured NRK-52E cells. Furthermore, we speculated that TGF-beta played a pathogenic role in Ang II-induced CKD because TGF-beta induced the activation of NLRP3 inflammasomes and Gasdermin D cleavage expression. We also proved that the pharmacological inhibition of NLRP3 by ISO caused a decrease in TGF-beta-induced NLRP3 inflammasome activation and the expression of EMT markers (alpha-SMA and CollagenI) and Gasdermin D cleavage. Collectively, these results suggest that TGF-beta-mediated NLRP3 inflammasome activation may cause the release of HMGB1 and an increase in Gasdermin D cleavage in NRK-52E, thereby contributing to renal fibrosis in Ang II-induced CKD. These findings provide novel insights into the pathogenic role of NLRP3 in CKD associated with high blood pressure.

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“…Activation of caspase-11 non-canonical inflammasome induces the proteolytic activation of gasdermin D (GSDMD) at the 276 aspartic acid residue to produce the N-terminal pore-forming domain and the C-terminal autoinhibitory domain of GSDMD. The N-terminal pore-forming domain of GSDMD (N-GSDMD) moves to the cell membrane to generate N-GSDMD-mediated large barrel-shaped transmembrane pores that are 27-fold symmetric oligomers [13]. The N-GSDMD pores are 18 nm in inner diameter and allow the secretion of a number of cytoplasmic molecules to the extracellular space including pro-inflammatory cytokines, IL-1β and IL-18.…”

Section: Caspase-11 Non-canonical Inflammasome-activated Inflammatorymentioning

confidence: 99%

“…The N-GSDMD pores are 18 nm in inner diameter and allow the secretion of a number of cytoplasmic molecules to the extracellular space including pro-inflammatory cytokines, IL-1β and IL-18. N-GSDMD pores also increase in osmotic pressure, leading to an influx of extracellular water followed by cell swelling, and eventually to cell lysis known as pyroptosis, an inflammatory form of apoptosis [12][13][14]37]. Pyroptosis is a part of the anti-microbial inflammatory response.…”

Section: Caspase-11 Non-canonical Inflammasome-activated Inflammatorymentioning

confidence: 99%

Caspase-11 Non-Canonical Inflammasome: Emerging Activator and Regulator of Infection-Mediated Inflammatory Responses

2020

IJMS

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Inflammation is a body's protective mechanism to eliminate invading pathogens and cellular damaging signals. The inflammatory response consists of two main consecutive steps-a priming step preparing the inflammatory responses and a triggering step boosting the inflammatory responses. The main feature of the triggering step is the activation of the inflammasome, an intracellular multiprotein complex facilitating the inflammatory responses. The regulatory roles of 'canonical' inflammasomes in the inflammatory responses and diseases have been largely investigated, so far. New types of inflammasomes have been recently discovered and named as 'non-canonical' inflammasomes since their roles to induce inflammatory responses are similar to those of canonical inflammasomes, however, the stimulating ligands and the underlying mechanisms are different. Therefore, a growing number of studies have actively investigated the novel roles of non-canonical inflammasomes in inflammatory responses and diseases. This review summarizes and discusses the recent studies exploring the regulatory roles of caspase-11 non-canonical inflammasome during the inflammatory responses and provides insight into the development of novel therapeutics for infectious and inflammatory diseases by targeting caspase-11 non-canonical inflammasome.

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Mechanism and Regulation of Gasdermin-Mediated Cell Death

Cited by 116 publications

References 86 publications

<p>Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis</p>

<p>Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis</p>

Contribution of TGF-Beta-Mediated NLRP3-HMGB1 Activation to Tubulointerstitial Fibrosis in Rat With Angiotensin II-Induced Chronic Kidney Disease

Caspase-11 Non-Canonical Inflammasome: Emerging Activator and Regulator of Infection-Mediated Inflammatory Responses

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