Mouse of the Month
Pyroptosis executor: gasdermin D (GSDMD)
Pyroptosis has known as an inflammation-inducible genetically programmed cell death since it was first reported as a characteristic cell death observed in microbial-infected macrophages1)2)3). Pyroptosis response is regulated by specific caspases including casapase-1 and their substrates, gasdermin D (Gsdmd/GSDMD)4)5)6). This gene is a member of a novel gene-family, Gsdm/GSDM, which depositor Dr. Shiroishi (during belong to NIG) and his colleague found and gave the name7)8). The pytoptosis pathway is roughly as follows: (1) response to foreign antigen in immunocompetent cells (macrophages, dendritic cells, T cells, etc.); (2) activation of caspases; (3) GSDMD cleavage by caspases; (4) Multimerization of activated N-terminal GSDMD fragments and insertion to plasma membrane; (5) plasma membrane pore-forming9); (6) necrosis-like cell morphologic changes (plasma membrane permeabilization, cellular swelling and rupture, etc.). Eventually, released cellular constituents including inflammatory cytokines evoke the inflammation into surrounding cells.
From RIKEN BRC Experimental Animal Division, Gsdmd-deficient mice (RBRC10761) and Gsdmd-floxed mice (RBRC10762) are available10). These strains were contributed to the recent result that caspase-1 induces apoptosis or pyroptosis with dependence on Gsdmd/GSDMD11). In summary, caspase-1 triggers apoptosis at GSDMD-low/deficient cell types like neurons, apart from GSDMD-dependent pyroptosis. The GSDMD-independent apoptosis is suggested to be related with the onset of neurodegenerative diseases (cerebral infarction, Alzheimer’s disease, amyotrophic lateral sclerosis, and so on). Therefore, Gsdmd gene-modified mice will be useful for not only understanding of life phenomenon but also exploration of a novel therapeutic target for such disease.
In addition, Gsdma (a member of the gasdermin gene family) LacZ-KI mice (RBRC10760) are also deposited12). Though Gsdma/GSDMA expression was observed in epithelial tissue, the relationship between GSDMA and programmed cell death has not been revealed yet. However, it was reported that N-terminal GSDMA fragment possess plasma membrane pore forming capability similar to N-terminal GSDMD fragment13).
|Depositor||:||Toshihiko Shiroishi, Ph.D.
National Institute of Genetics, Research Organization of Information and Systems
(at the time of the strain deposition)
(Gsdmd gene-deficient mice)
(Gsdmd gene-floxed mice)
(Gsdma gene-deficient mice)
Macrophages are sensitive to anthrax lethal toxin through an acid-dependent process.
J Biol Chem.; 1986 Jun 5;261(16):7123-6.
|||Zychlinsky A, Prevost MC, Sansonetti PJ.
Shigella flexneri induces apoptosis in infected macrophages.
Nature. 1992 Jul 9;358(6382):167-9.
|||Cookson BT, Brennan MA.
Pro-inflammatory programmed cell death.
Trends Microbiol. 2001 Mar;9(3):113-4.
|||Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, Liu PS, Lill JR, Li H, Wu J, Kummerfeld S, Zhang J, Lee WP, Snipas SJ, Salvesen GS, Morris LX, Fitzgerald L, Zhang Y, Bertram EM, Goodnow CC, Dixit VM.
Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling.
Nature. 2015 Oct 29;526(7575):666-71.
|||Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F.
Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.
Nature. 2015 Oct 29;526(7575):660-5.
|||Broz P, Pelegrín P, Shao F.
The gasdermins, a protein family executing cell death and inflammation.
Nat Rev Immunol. 2020 Mar;20(3):143-157.
|||Saeki N, Kuwahara Y, Sasaki H, Satoh H, Shiroishi T.
Gasdermin (Gsdm) localizing to mouse chromosome 11 is predominantly expressed in upper gastrointestinal tract but significantly suppressed in human gastric cancer cells.
Mamm. Genome 2000 Sep; 11(9):718-724.
|||Tamura M, Tanaka S, Fujii T, Aoki A, Komiyama H, Ezawa K, Sumiyama K, Sagai T, Shiroishi T.
Members of a novel gene family, Gsdm, are expressed exclusively in the epithelium of the skin and gastrointestinal tract in a highly tissue-specific manner.
Genomics. 2007 May;89(5):618-29.
|||Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, Sun H, Wang DC, Shao F.
Pore-forming activity and structural autoinhibition of the gasdermin family.
Nature. 2016 Jul 7;535(7610):111-6.
|||Fujii T, Tamura M, Tanaka S, Kato Y, Yamamoto H, Mizushina Y, Shiroishi T.
Gasdermin D (Gsdmd) is dispensable for mouse intestinal epithelium development.
Genesis. 2008 Aug;46(8):418-23.
|||Tsuchiya K, Nakajima S, Hosojima S, Thi Nguyen D, Hattori T, Manh Le T, Hori O, Mahib MR, Yamaguchi Y, Miura M, Kinoshita T, Kushiyama H, Sakurai M, Shiroishi T, Suda T.
Caspase-1 initiates apoptosis in the absence of gasdermin D.
Nat Commun. 2019 May 7;10(1):2091.
|||Tanaka S, Mizushina Y, Kato Y, Tamura M, Shiroishi T.
Functional conservation of Gsdma cluster genes specifically duplicated in the mouse genome.
G3 (Bethesda). 2013 Oct 3;3(10):1843-50.
|||Ruan J, Xia S, Liu X, Lieberman J, Wu H.
Cryo-EM structure of the gasdermin A3 membrane pore.
Nature. 2018 May;557(7703):62-67.
Saori Mizuno, Ph.D.
Contact: Experimental Animal Division, RIKEN BioResource Research Center (firstname.lastname@example.org)
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