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1.C.123 The Pore-forming Gasdermin (Gasdermin) Family 

Pyroptosis was long regarded as caspase-1-mediated monocyte death in response to certain bacterial insults. Caspase-1 is activated upon various infectious and immunological challenges through different inflammasomes. The discovery of caspase-11/4/5 function in sensing intracellular lipopolysaccharide expanded the spectrum of pyroptosis mediators and also revealed that pyroptosis is not cell type specific. The pyroptosis executioner, gasdermin D (GSDMD), is a substrate of both caspase-1 and caspase-11/4/5 and is in the large gasdermin family bearing membrane pore-forming activity (Shi et al. 2016). Thus, pyroptosis is defined as gasdermin-mediated programmed necrosis.  These proteins are associated with various genetic diseases.

The N-terminal domain of Gasdermin-D promotes pyroptosis in response to microbial infection and danger signals. The active protein is produced by the cleavage of gasdermin-D by inflammatory caspases CASP1 or CASP4 in response to canonical, as well as non-canonical (such as cytosolic LPS) inflammasome activators (Shi et al. 2015; Kayagaki et al. 2015; Sborgi et al. 2016). After cleavage, the product moves to the plasma membrane where it binds to inner leaflet lipids, including monophosphorylated phosphatidylinositols, as well as phosphatidic acid and phosphatidylserine (Ding et al. 2016). Homooligomerization within the membrane generates pores of 10 - 15 nanometers (nm) (inner diameter), allowing the release of mature IL1B and triggering pyroptosis (Sborgi et al. 2016; Ding et al. 2016).It thus exhibits bactericidal activity. The N-terminal domain of Gasdermin-D, released from pyroptotic cells into the extracellular milieu rapidly binds to and kills both Gram-negative and Gram-positive bacteria, without harming neighboring mammalian cells, as it does not disrupt the plasma membrane from the outside due to lipid-binding specificity (Ding et al. 2016). Strongly binds to bacterial and mitochondrial lipids, including cardiolipin. Does not bind to unphosphorylated phosphatidylinositol, phosphatidylethanolamine or phosphatidylcholine (Ding et al. 2016).

The reactions catalyzed by Gasdermins is:

Solutes (in) → Solutes (out)

References associated with 1.C.123 family:

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Op de Beeck, K., G. Van Camp, S. Thys, N. Cools, I. Callebaut, K. Vrijens, L. Van Nassauw, V.F. Van Tendeloo, J.P. Timmermans, and L. Van Laer. (2011). The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein. Eur J Hum Genet 19: 965-973. 21522185
Sborgi, L., S. Rühl, E. Mulvihill, J. Pipercevic, R. Heilig, H. Stahlberg, C.J. Farady, D.J. Müller, P. Broz, and S. Hiller. (2016). GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO. J. 35: 1766-1778. 27418190
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