Chopping
            <scp>GSDMD</scp>
            : caspase‐8 has joined the team of pyroptosis‐mediating caspases

Gram, Anna M.; Booty, Lee M.; Bryant, Clare

doi:10.15252/embj.2019102065

Cited by 30 publications

(23 citation statements)

References 11 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, it was shown that caspase-8 also cleaves GSDMD, leading to caspase-8-mediated GSDMD-dependent cell death in response to extrinsic triggers of apoptosis [16]. This form of pyroptosis is induced by inhibition of pro-survival signals, mainly by pharmaceutical or bacterial targeting of TAK1 kinase [[17], [18], [19]].…”

Section: Pyroptosismentioning

confidence: 99%

Programmed necrotic cell death of macrophages: Focus on pyroptosis, necroptosis, and parthanatos

et al. 2019

View full text Add to dashboard Cite

Macrophages are highly plastic cells of the innate immune system. Macrophages play central roles in immunity against microbes and contribute to a wide array of pathologies. The processes of macrophage activation and their functions have attracted considerable attention from life scientists. Although macrophages are highly resistant to many toxic stimuli, including oxidative stress, macrophage death has been reported in certain diseases, such as viral infections, tuberculosis, atherosclerotic plaque development, inflammation, and sepsis. While most studies on macrophage death focused on apoptosis, a significant body of data indicates that programmed necrotic cell death forms may be equally important modes of macrophage death. Three such regulated necrotic cell death modalities in macrophages contribute to different pathologies, including necroptosis, pyroptosis, and parthanatos. Various reactive oxygen and nitrogen species, such as superoxide, hydrogen peroxide, and peroxynitrite have been shown to act as triggers, mediators, or modulators in regulated necrotic cell death pathways. Here we discuss recent advances in necroptosis, pyroptosis, and parthanatos, with a strong focus on the role of redox homeostasis in the regulation of these events.

show abstract

Section: Pyroptosismentioning

confidence: 99%

Programmed necrotic cell death of macrophages: Focus on pyroptosis, necroptosis, and parthanatos

et al. 2019

View full text Add to dashboard Cite

show abstract

“…To investigate the type of cell death that occurs when one or more programmed cell death pathway is blocked in S. Typhimurium infected macrophages, Doerflinger and colleagues performed immunoblots to monitor the processing and activation of key cell death pathway components. Although caspase-8 has previously been reported to activate pyroptotic cell death by processing the effector of pyroptosis GSDMD (Gram et al, 2019), the authors found that GSDMD was not processed in infected Casp1 À/À Casp11 À/À BMDMs, indicating that pyroptosis was not occurring in the absence of Casp1 and Casp11. Instead, caspase-8, caspase-9, and executioner caspase-3 and caspase-7 were cleaved in infected Casp1 À/À Casp11 À/À Casp12 À/À BMDMs, indicating that caspase-8dependent apoptosis was contributing to the cell death (Figure 1, upper right).…”

mentioning

confidence: 83%

A Flexible and Deadly Way to Control Salmonella Infection

Kinsella

Stallings

2020

Immunity

View full text Add to dashboard Cite

Although programmed cell death can control intracellular bacterial replication, the role of cell death during systemic Salmonella infection remained elusive. In this issue of Immunity, Doerflinger et al. discover a critical but overlapping role for cell death associated caspases during Salmonella infection.Programmed cell death is one mechanism by which the host controls intracellular pathogen replication, in part by eliminating the replicative niche (Miao et al., 2010). Salmonella enterica serovar Typhimurium (S. Typhimurium) is an important intracellular Gram-negative bacterial pathogen that primarily infects phagocytes and can cause typhoid fever, a systemic infection that affects 10-20 million people globally (Kupz et al., 2014). One form of cell death referred to as ''pyroptosis'' is induced in phagocytes infected with S. Typhimurium through inflammasome-dependent activation of caspase-1 or lipopolysaccharide-induced activation of caspase-11 (Broz et al., 2010). Caspase-1 or caspase-11 can process gasdermin D (GSDMD), which self assembles into a pore that inserts into the plasma membrane resulting in pyroptosis (Negroni et al., 2015) (Figure 1, upper left). Casp1 À/À Casp11 À/À macrophages resist S. Typhimurium induced cell death in vitro (Broz et al., 2012), suggesting pyroptosis contributes to cell death during S. Typhimurium infection. However, in a model for the systemic phase of typhoid fever where mice are infected with an attenuated strain of S. Typhimurium intravenously, Casp1 À/À Casp11 À/À mice are still able to clear the infection by 12 weeks post-infection (Doerflinger et al., 2020;Kupz et al., 2014). Additional deletion of the close homolog caspase-12 also had no added effect on clearance of S. Typhimurium. This suggests that either cell death is not required for control of S. Typhimurium in this model or that alternative programmed cell death pathways compensate for the loss of pyroptosis. Indeed, in this issue of Immunity (Doerflinger et al., 2020), Doerflinger et al. find that

show abstract

“…Pro-apoptotic caspases including caspase-3 and caspase-8 are implicated in the regulation of GSDMD in macrophages by current findings. Caspase-8 is long known for its role in the control of apoptotic cell death, however, emerging studies are unveiling its role in pyroptotic cell death as well during specific inflammatory responses and pathogenic infections [32][33][34][35]. It catalyzes GSDMD to produce active p30 fragments that drive cell death in macrophages morphologically similar to pyroptosis, however, cleavage of GSDMD into p20 and p43 fragments were also observed which was suggested to be carried out by caspase-3.…”

Section: Gasdermins Induce Pyroptosis Using Inflammatory Caspases Pro-caspases and Granzymesmentioning

confidence: 99%

Molecular and structural aspects of gasdermin family pores and insights into gasdermin-elicited programmed cell death

Zahid

Ismail

Jin

2021

Biochemical Society Transactions

View full text Add to dashboard Cite

Pyroptosis is a highly inflammatory and lytic type of programmed cell death (PCD) commenced by inflammasomes, which sense perturbations in the cytosolic environment. Recently, several ground-breaking studies have linked a family of pore-forming proteins known as gasdermins (GSDMs) to pyroptosis. The human genome encodes six GSDM proteins which have a characteristic feature of forming pores in the plasma membrane resulting in the disruption of cellular homeostasis and subsequent induction of cell death. GSDMs have an N-terminal cytotoxic domain and an auto-inhibitory C-terminal domain linked together through a flexible hinge region whose proteolytic cleavage by various enzymes releases the N-terminal fragment that can insert itself into the inner leaflet of the plasma membrane by binding to acidic lipids leading to pore formation. Emerging studies have disclosed the involvement of GSDMs in various modalities of PCD highlighting their role in diverse cellular and pathological processes. Recently, the cryo-EM structures of the GSDMA3 and GSDMD pores were resolved which have provided valuable insights into the pore formation process of GSDMs. Here, we discuss the current knowledge regarding the role of GSDMs in PCD, structural and molecular aspects of autoinhibition, and pore formation mechanism followed by a summary of functional consequences of gasdermin-induced membrane permeabilization.

show abstract

Chopping GSDMD : caspase‐8 has joined the team of pyroptosis‐mediating caspases

Cited by 30 publications

References 11 publications

Programmed necrotic cell death of macrophages: Focus on pyroptosis, necroptosis, and parthanatos

Programmed necrotic cell death of macrophages: Focus on pyroptosis, necroptosis, and parthanatos

A Flexible and Deadly Way to Control Salmonella Infection

Molecular and structural aspects of gasdermin family pores and insights into gasdermin-elicited programmed cell death

Contact Info

Product

Resources

About