Gasdermins mediate cellular release of mitochondrial DNA during pyroptosis and apoptosis

Torre‐Minguela, Carlos de; Gómez, Ana Isabel Sanz; Couillin, Isabelle; Pelegrı́n, Pablo

doi:10.1096/fj.202100085r

Cited by 61 publications

(54 citation statements)

References 54 publications

(129 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pyroptosis and intrinsic apoptosis are two forms of regulated cell death driven by active caspases. Caspase-1 induces GSDMD pore formation during pyroptosis, whereas caspase-3 promotes GSDME pore formation during apoptosis [ 31 ]. Our results showed that TNF-α activated caspase-3, and further induced GSDME-mediated pyroptosis in HUVECs.…”

Section: Discussionmentioning

confidence: 99%

HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells

et al. 2022

View full text Add to dashboard Cite

Histone deacetylase 11 (HDAC11), a sole member of the class IV HDAC subfamily, participates in various cardiovascular diseases. Recent evidence showed that pyroptosis was a form of inflammatory programmed cell death and is critical for atherosclerosis (AS). However, little is known about the effect of HDAC11 on endothelial cell pyroptosis in AS. Thus, this study aims to investigate the role of HDAC11 in vascular endothelial cell pyroptosis and its molecular mechanism. Firstly, we found that HDAC11 expression was up-regulated and pyroptosis occurred in the aorta of ApoE−/− mice fed with a high-fat diet (HFD) for 8 or 12 weeks. Then, in vitro study found the treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α) resulted in pyroptosis, as evidenced by activation of caspase-1 and caspase-3 activation, cleavage of downstream gasdermin D (GSDMD) and gasdermin E (GSDME/DFNA5), the release of pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and IL-18, as well as elevation of LDH activity and increase of propidium iodide (PI)-positive cells. Besides, TNF-α increased HDAC11 expression and induced pyroptosis via TNFR1 in HUVECs. HDAC11 knockdown mitigated pyroptosis by suppressing both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways in TNF-α-induced HUVECs. Moreover, GSDME knockdown by siRNA significantly decreased pyroptosis and inflammatory response, while treatment with disulfiram or necrosulfonamide (NSA) further augmented the inhibitory effects of GSDME siRNA on pyroptosis and inflammatory response. Further studies found HDAC11 formed a complex with ERG and decreased the acetylation levels of ERG. More importantly, ERG knockdown augmented vascular endothelial cell pyroptosis in TNF-α-induced HUVECs. Taken together, our study suggests that HDAC11 might promote both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways leading to pyroptosis via regulation of ERG acetylation in HUVECs. Modulation of HDAC11 may serve as a potential target for therapeutic strategies of AS.

show abstract

Section: Discussionmentioning

confidence: 99%

HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Regardless of cancer cells or normal cells, GSDME-mediated pyroptosis is closely associated with mitochondrial apoptosis. The pore-forming activity of GSDME-N extends beyond the cell membrane to the mitochondrial membrane, which permeabilizes mitochondria to release cytochrome C and mtDNA ( Rogers et al, 2019 ; de Torre-Minguela et al, 2021 ). The crosstalk between GDSME and GSDMD, which are the crucial proteins in the gasdermin family mediating pyroptosis, deserves attention.…”

Section: Discussionmentioning

confidence: 99%

“…Another research further indicated that GSDME-N permeates mitochondria preferentially, and ruptures the plasma membrane later ( Rogers and Alnemri, 2019 ). Mitochondrial DNA (mtDNA), as a DAMP, is released out of the mitochondria in the pore formation constructed by GSDME-N, and removed extracellularly upon rupture of the plasma membrane ( de Torre-Minguela et al, 2021 ). Additionally, GSDME-N also induces mitochondrial network fragmentation during pyroptosis and apoptosis ( de Torre-Minguela et al, 2021 ).…”

Section: Gsdme-mediated Programmed Cell Deathmentioning

confidence: 99%

“…Mitochondrial DNA (mtDNA), as a DAMP, is released out of the mitochondria in the pore formation constructed by GSDME-N, and removed extracellularly upon rupture of the plasma membrane ( de Torre-Minguela et al, 2021 ). Additionally, GSDME-N also induces mitochondrial network fragmentation during pyroptosis and apoptosis ( de Torre-Minguela et al, 2021 ). Above all, as a novel mitochondrial pore-forming protein, GSDME is essential for the crosstalk between pyroptotic and apoptotic cell death pathways.…”

Section: Gsdme-mediated Programmed Cell Deathmentioning

confidence: 99%

See 1 more Smart Citation

Gasdermin E: A Prospective Target for Therapy of Diseases

et al. 2022

View full text Add to dashboard Cite

Gasdermin E (GSDME) is a member of the gasdermin protein family, which mediates programmed cell death including apoptosis and pyroptosis. Recently, it was suggested that GSDME is activated by chemotherapeutic drugs to stimulate pyroptosis of cancer cells and trigger anti-tumor immunity, which is identified as a tumor suppressor. However, GSDME-mediated pyroptosis contributes to normal tissue damage, leading to pathological inflammations. Inhibiting GSDME-mediated pyroptosis might be a potential target in ameliorating inflammatory diseases. Therefore, targeting GSDME is a promising option for the treatment of diseases in the future. In this review, we introduce the roles of GSDME-driven programmed cell death in different diseases and the potential targeted therapies of GSDME, so as to provide a foundation for future research.

show abstract

“…Although this was a useful distinction, the historic application of the term “apoptosis” to target cell death upon CTL attack does not imply that it meets the stringent molecular criteria for apoptosis as it is defined today, nor that other related RCD modalities have been excluded. Many classical morphological and molecular features of apoptosis such as membrane blebbing, caspase-3/6/8/9 activation, PARP cleavage, PS exposure, mitochondrial permeabilization, and DNA fragmentation can be shared with other RCD modalities, and thus conventional apoptosis assays such as AnnexinV and TUNEL staining are not specific for apoptosis ( 98 – 104 ). That is not to say, however, that apoptosis is not an important mechanism of cell death upon CTL attack; in all likelihood, the mechanism of target cell death may be context-dependent, and subject to change based upon the characteristics of both the CTL and target cell populations.…”

Section: Choreography Of the Target Cell Response To Ctl Attackmentioning

confidence: 99%

Greek Fire, Poison Arrows, and Scorpion Bombs: How Tumor Cells Defend Against the Siege Weapons of Cytotoxic T Lymphocytes

2022

View full text Add to dashboard Cite

CD8+ cytotoxic T lymphocytes (CTLs) are the main cellular effectors of the adaptive immune response against cancer cells, which in turn have evolved sophisticated cellular defense mechanisms to withstand CTL attack. Herein we provide a critical review of the pertinent literature on early and late attack/defense events taking place at the CTL/target cell lytic synapse. We examine the earliest steps of CTL-mediated cytotoxicity (“the poison arrows”) elicited within seconds of CTL/target cell encounter, which face commensurately rapid synaptic repair mechanisms on the tumor cell side, providing the first formidable barrier to CTL attack. We examine how breach of this first defensive barrier unleashes the inextinguishable “Greek fire” in the form of granzymes whose broad cytotoxic potential is linked to activation of cell death executioners, injury of vital organelles, and destruction of intracellular homeostasis. Herein tumor cells deploy slower but no less sophisticated defensive mechanisms in the form of enhanced autophagy, increased reparative capacity, and dysregulation of cell death pathways. We discuss how the newly discovered supra-molecular attack particles (SMAPs, the “scorpion bombs”), seek to overcome the robust defensive mechanisms that confer tumor cell resistance. Finally, we discuss the implications of the aforementioned attack/defense mechanisms on the induction of regulated cell death (RCD), and how different contemporary RCD modalities (including apoptosis, pyroptosis, and ferroptosis) may have profound implications for immunotherapy. Thus, we propose that understanding and targeting multiple steps of the attack/defense process will be instrumental to enhance the efficacy of CTL anti-tumor activity and meet the outstanding challenges in clinical immunotherapy.

show abstract

Gasdermins mediate cellular release of mitochondrial DNA during pyroptosis and apoptosis

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 61 publications

References 54 publications

HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells

HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells

Gasdermin E: A Prospective Target for Therapy of Diseases

Greek Fire, Poison Arrows, and Scorpion Bombs: How Tumor Cells Defend Against the Siege Weapons of Cytotoxic T Lymphocytes

Contact Info

Product

Resources

About