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

Symmank, Judit; Jacobs, Collin; Schulze‐Späte, Ulrike

doi:10.1038/s41392-022-01011-0

Cited by 3 publications

(4 citation statements)

References 5 publications

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“…Thereby GSDMA acts as a sensor for the pathogen. Moreover, cleavage at Gln246 induces GSDMA activation and pyroptosis, demonstrating that GSDMA also acts as an effector ( 80 , 84 ). In mice, SpeB cleaves and activates GsdmA1.…”

Section: Gsdmamentioning

confidence: 98%

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The gasdermins: a pore-forming protein family expressed in the epidermis

Slaufova,

Karakaya,

Di Filippo

et al. 2023

Front. Immunol.

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Gasdermins comprise a family of pore-forming proteins, which play critical roles in (auto)inflammatory diseases and cancer. They are expressed as self-inhibited precursor proteins consisting of an aminoterminal cytotoxic effector domain (NT-GSDM) and a carboxyterminal inhibitor domain (GSDM-CT) separated by an unstructured linker region. Proteolytic processing in the linker region liberates NT-GSDM, which translocates to membranes, forms oligomers, and induces membrane permeabilization, which can disturb the cellular equilibrium that can lead to cell death. Gasdermin activation and pore formation are associated with inflammation, particularly when induced by the inflammatory protease caspase-1 upon inflammasome activation. These gasdermin pores allow the release of the pro-inflammatory cytokines interleukin(IL)-1β and IL-18 and induce a lytic type of cell death, termed pyroptosis that supports inflammation, immunity, and tissue repair. However, even at the cellular level, the consequences of gasdermin activation are diverse and range from induction of programmed cell death - pyroptosis or apoptosis - to poorly characterized protective mechanisms. The specific effects of gasdermin activation can vary between species, cell types, the membrane that is being permeabilized (plasma membrane, mitochondrial membrane, etc.), and the overall biological state of the local tissue/cells. In epithelia, gasdermins seem to play crucial roles. Keratinocytes represent the main cell type of the epidermis, which is the outermost skin layer with an essential barrier function. Compared to other tissues, keratinocytes express all members of the gasdermin family, in part in a differentiation-specific manner. That raises questions regarding the specific roles of individual GSDM family members in the skin, the mechanisms and consequences of their activation, and the potential crosstalk between them. In this review, we summarize the current knowledge about gasdermins with a focus on keratinocytes and the skin and discuss the possible roles of the different family members in immunity and disease.

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Section: Gsdmamentioning

confidence: 98%

“…Until recently, neither a biological function of GSDMA nor an activating protease was known ( 84 ). Interestingly, two groups have shown that in keratinocytes, GSDMA is cleaved and activated by a pathogen-derived protease called SpeB, a virulence factor of the Gram-positive Group A Streptococcus (GAS) ( 80 , 81 ).…”

Section: Gsdmamentioning

confidence: 99%

The gasdermins: a pore-forming protein family expressed in the epidermis

Slaufova,

Karakaya,

Di Filippo

et al. 2023

Front. Immunol.

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show abstract

“…Neutrophil elastase and cathepsin G can directly cleave GSDMD to activate pyroptosis [ 43 ]. Streptococcus pyogenes expresses a cysteine protease SpeB virulence factor that triggers pyroptosis by cleaving GSDMA after Gln246 [ 44 , 45 ]. GSDMC can be cleaved by caspase 8 upon triggering of tumor necrosis factor (TNF) mediated death receptor signaling, converting apoptosis to pyroptosis in GSDMC-expressing cells [ 46 ].…”

Section: Pyroptosismentioning

confidence: 99%

Pyroptosis and degenerative diseases of the elderly

et al. 2023

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Pyroptosis is a recently described mechanism of programmed cell death mediated by proteins of the gasdermin family. Widely recognized signaling cascades include the classical, non-classical, caspase-3-dependent gasdermin E and caspase-8-dependent gasdermin D pathways. Additional pyroptotic pathways have been subsequently reported. With the rising prevalence of advanced age, the role of pyroptosis in the degenerative diseases of the elderly has attracted increased research attention. This article reviews the primary mechanisms of pyroptosis and summarizes progress in the research of degenerative diseases of the elderly such as presbycusis, age-related macular degeneration, Alzheimer’s disease, intervertebral disc degeneration, and osteoarthritis.

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“…In mice, three isoforms of Gsdma (Gsdma1–3) and four isoforms of Gsdmc (Gsdmc1–4) are present ( 57 ), while Gsdmb is not observed. Streptococcus A secretes the protease streptococcal exotoxin B (SpeB), which can directly cleave GSDMA to activate pyroptosis ( 58 ). Recent studies have found that GSDMA-deficient mice are susceptible to streptococcal infection in a SpeB-dependent manner ( 59 , 60 ).…”

Section: Inflammasome-mediated Pyroptosismentioning

confidence: 99%

Inflammasome and pyroptosis in autoimmune liver diseases

et al. 2023

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Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and IgG4-related sclerosing cholangitis (IgG4-SC) are the four main forms of autoimmune liver diseases (AILDs), which are all defined by an aberrant immune system attack on the liver. Most previous studies have shown that apoptosis and necrosis are the two major modes of hepatocyte death in AILDs. Recent studies have reported that inflammasome-mediated pyroptosis is critical for the inflammatory response and severity of liver injury in AILDs. This review summarizes our present understanding of inflammasome activation and function, as well as the connections among inflammasomes, pyroptosis, and AILDs, thus highlighting the shared features across the four disease models and gaps in our knowledge. In addition, we summarize the correlation among NLRP3 inflammasome activation in the liver-gut axis, liver injury, and intestinal barrier disruption in PBC and PSC. We summarize the differences in microbial and metabolic characteristics between PSC and IgG4-SC, and highlight the uniqueness of IgG4-SC. We explore the different roles of NLRP3 in acute and chronic cholestatic liver injury, as well as the complex and controversial crosstalk between various types of cell death in AILDs. We also discuss the most up-to-date developments in inflammasome- and pyroptosis-targeted medicines for autoimmune liver disorders.

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

Cited by 3 publications

References 5 publications

The gasdermins: a pore-forming protein family expressed in the epidermis

The gasdermins: a pore-forming protein family expressed in the epidermis

Pyroptosis and degenerative diseases of the elderly

Inflammasome and pyroptosis in autoimmune liver diseases

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