| Structural highlights
Disease
GSDME_HUMAN Rare autosomal dominant non-syndromic sensorineural deafness type DFNA. The disease is caused by variants affecting the gene represented in this entry. Is a tumor suppressor gene with an important role in colorectal cancer (CRC).[1]
Function
Q6J2R6_DANRE GSDME_HUMAN Precursor of a pore-forming protein that converts non-inflammatory apoptosis to pyroptosis (PubMed:27281216, PubMed:28459430, PubMed:33852854, PubMed:35594856, PubMed:36607699). This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-E, N-terminal) binds to membranes and forms pores, triggering pyroptosis (PubMed:28459430).[2] [3] [4] [5] [6] Pore-forming protein produced by cleavage by CASP3 or granzyme B (GZMB), which converts non-inflammatory apoptosis to pyroptosis or promotes granzyme-mediated pyroptosis, respectively (PubMed:27281216, PubMed:28459430, PubMed:32188940, PubMed:33852854, PubMed:35594856). After cleavage, moves to the plasma membrane, homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the release of mature interleukins (IL1B and IL16) and triggering pyroptosis (PubMed:28459430, PubMed:32188940, PubMed:33852854, PubMed:35594856). Binds to inner leaflet lipids, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate (PubMed:28459430). Cleavage by CASP3 switches CASP3-mediated apoptosis induced by TNF or danger signals, such as chemotherapy drugs, to pyroptosis (PubMed:27281216, PubMed:28459430, PubMed:32188940). Mediates secondary necrosis downstream of the mitochondrial apoptotic pathway and CASP3 activation as well as in response to viral agents (PubMed:28045099). Exhibits bactericidal activity (PubMed:27281216). Cleavage by GZMB promotes tumor suppressor activity by triggering robust anti-tumor immunity (PubMed:21522185, PubMed:32188940). Suppresses tumors by mediating granzyme-mediated pyroptosis in target cells of natural killer (NK) cells: cleavage by granzyme B (GZMB), delivered to target cells from NK-cells, triggers pyroptosis of tumor cells and tumor suppression (PubMed:31953257, PubMed:32188940). May play a role in the p53/TP53-regulated cellular response to DNA damage (PubMed:16897187).[7] [8] [9] [10] [11] [12] [13] [14] [15] (Microbial infection) Pore-forming protein, which promotes maternal placental pyroptosis in response to Zika virus infection, contributing to adverse fetal outcomes.[16] GSDMD_MOUSE Gasdermin-D, N-terminal: Promotes pyroptosis in response to microbial infection and danger signals. 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 (PubMed:26611636, PubMed:26375259, PubMed:26375003, PubMed:27418190, PubMed:27385778, PubMed:27383986). After cleavage, moves to the plasma membrane where it strongly binds to membrane inner leaflet lipids, including monophosphorylated phosphatidylinositols, such as phosphatidylinositol 4-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate, as well as phosphatidylinositol (3,4,5)-trisphosphate, and more weakly to phosphatidic acid and phosphatidylserine. Homooligomerizes within the membrane and forms pores of 10 - 15 nanometers (nm) of inner diameter, allowing the release of mature IL1B and triggering pyroptosis. Exhibits bactericidal activity. Gasdermin-D, N-terminal 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. Under cell culture conditions, also active against intracellular bacteria, such as Listeria monocytogenes. Strongly binds to bacterial and mitochondrial lipids, including cardiolipin. Does not bind to phosphatidylethanolamine or phosphatidylcholine (PubMed:27383986).[17] [18] [19] [20] [21] [22]
References
- ↑ Kim MS, Chang X, Yamashita K, Nagpal JK, Baek JH, Wu G, Trink B, Ratovitski EA, Mori M, Sidransky D. Aberrant promoter methylation and tumor suppressive activity of the DFNA5 gene in colorectal carcinoma. Oncogene. 2008 Jun 5;27(25):3624-34. PMID:18223688 doi:10.1038/sj.onc.1211021
- ↑ 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. PMID:27281216 doi:https://dx.doi.org/10.1038/nature18590
- ↑ Wang Y, Gao W, Shi X, Ding J, Liu W, He H, Wang K, Shao F. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017 Jul 6;547(7661):99-103. PMID:28459430 doi:10.1038/nature22393
- ↑ Zhou B, Abbott DW. Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases. Cell Rep. 2021 Apr 13;35(2):108998. PMID:33852854 doi:10.1016/j.celrep.2021.108998
- ↑ Planès R, Pinilla M, Santoni K, Hessel A, Passemar C, Lay K, Paillette P, Valadão AC, Robinson KS, Bastard P, Lam N, Fadrique R, Rossi I, Pericat D, Bagayoko S, Leon-Icaza SA, Rombouts Y, Perouzel E, Tiraby M, Zhang Q, Cicuta P, Jouanguy E, Neyrolles O, Bryant CE, Floto AR, Goujon C, Lei FZ, Martin-Blondel G, Silva S, Casanova JL, Cougoule C, Reversade B, Marcoux J, Ravet E, Meunier E. Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells. Mol Cell. 2022 Jul 7;82(13):2385-2400.e9. PMID:35594856 doi:10.1016/j.molcel.2022.04.033
- ↑ Ren Y, Feng M, Hao X, Liu X, Li J, Li P, Gao J, Qi Q, Du L, Wang C, Wang Q, Wang Y. USP48 Stabilizes Gasdermin E to Promote Pyroptosis in Cancer. Cancer Res. 2023 Apr 4;83(7):1074-1093. PMID:36607699 doi:10.1158/0008-5472.CAN-22-1812
- ↑ Masuda Y, Futamura M, Kamino H, Nakamura Y, Kitamura N, Ohnishi S, Miyamoto Y, Ichikawa H, Ohta T, Ohki M, Kiyono T, Egami H, Baba H, Arakawa H. The potential role of DFNA5, a hearing impairment gene, in p53-mediated cellular response to DNA damage. J Hum Genet. 2006;51(8):652-664. PMID:16897187 doi:10.1007/s10038-006-0004-6
- ↑ Op de Beeck K, Van Camp G, Thys S, Cools N, Callebaut I, Vrijens K, Van Nassauw L, Van Tendeloo VF, Timmermans JP, Van Laer L. The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein. Eur J Hum Genet. 2011 Sep;19(9):965-73. PMID:21522185 doi:10.1038/ejhg.2011.63
- ↑ 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. PMID:27281216 doi:https://dx.doi.org/10.1038/nature18590
- ↑ Rogers C, Fernandes-Alnemri T, Mayes L, Alnemri D, Cingolani G, Alnemri ES. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat Commun. 2017 Jan 3;8:14128. PMID:28045099 doi:10.1038/ncomms14128
- ↑ Wang Y, Gao W, Shi X, Ding J, Liu W, He H, Wang K, Shao F. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017 Jul 6;547(7661):99-103. PMID:28459430 doi:10.1038/nature22393
- ↑ Liu Y, Fang Y, Chen X, Wang Z, Liang X, Zhang T, Liu M, Zhou N, Lv J, Tang K, Xie J, Gao Y, Cheng F, Zhou Y, Zhang Z, Hu Y, Zhang X, Gao Q, Zhang Y, Huang B. Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. Sci Immunol. 2020 Jan 17;5(43):eaax7969. PMID:31953257 doi:10.1126/sciimmunol.aax7969
- ↑ Zhang Z, Zhang Y, Xia S, Kong Q, Li S, Liu X, Junqueira C, Meza-Sosa KF, Mok TMY, Ansara J, Sengupta S, Yao Y, Wu H, Lieberman J. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature. 2020 Mar;579(7799):415-420. PMID:32188940 doi:10.1038/s41586-020-2071-9
- ↑ Zhou B, Abbott DW. Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases. Cell Rep. 2021 Apr 13;35(2):108998. PMID:33852854 doi:10.1016/j.celrep.2021.108998
- ↑ Planès R, Pinilla M, Santoni K, Hessel A, Passemar C, Lay K, Paillette P, Valadão AC, Robinson KS, Bastard P, Lam N, Fadrique R, Rossi I, Pericat D, Bagayoko S, Leon-Icaza SA, Rombouts Y, Perouzel E, Tiraby M, Zhang Q, Cicuta P, Jouanguy E, Neyrolles O, Bryant CE, Floto AR, Goujon C, Lei FZ, Martin-Blondel G, Silva S, Casanova JL, Cougoule C, Reversade B, Marcoux J, Ravet E, Meunier E. Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells. Mol Cell. 2022 Jul 7;82(13):2385-2400.e9. PMID:35594856 doi:10.1016/j.molcel.2022.04.033
- ↑ Zhao Z, Li Q, Ashraf U, Yang M, Zhu W, Gu J, Chen Z, Gu C, Si Y, Cao S, Ye J. Zika virus causes placental pyroptosis and associated adverse fetal outcomes by activating GSDME. Elife. 2022 Aug 16;11:e73792. PMID:35972780 doi:10.7554/eLife.73792
- ↑ 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. doi: 10.1038/nature15514. Epub 2015 Sep 16. PMID:26375003 doi:https://dx.doi.org/10.1038/nature15514
- ↑ 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. doi: 10.1038/nature15541. Epub 2015 Sep 16. PMID:26375259 doi:https://dx.doi.org/10.1038/nature15541
- ↑ He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, Yang ZH, Zhong CQ, Han J. Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res. 2015 Dec;25(12):1285-98. doi: 10.1038/cr.2015.139. Epub 2015 Nov 27. PMID:26611636 doi:https://dx.doi.org/10.1038/cr.2015.139
- ↑ Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, Lieberman J. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016 Jul 7;535(7610):153-8. doi: 10.1038/nature18629. PMID:27383986 doi:https://dx.doi.org/10.1038/nature18629
- ↑ Russo HM, Rathkey J, Boyd-Tressler A, Katsnelson MA, Abbott DW, Dubyak GR. Active Caspase-1 Induces Plasma Membrane Pores That Precede Pyroptotic Lysis and Are Blocked by Lanthanides. J Immunol. 2016 Aug 15;197(4):1353-67. doi: 10.4049/jimmunol.1600699. Epub 2016, Jul 6. PMID:27385778 doi:https://dx.doi.org/10.4049/jimmunol.1600699
- ↑ Sborgi L, Ruhl S, Mulvihill E, Pipercevic J, Heilig R, Stahlberg H, Farady CJ, Muller DJ, Broz P, Hiller S. GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J. 2016 Aug 15;35(16):1766-78. doi: 10.15252/embj.201694696. Epub 2016 Jul, 14. PMID:27418190 doi:https://dx.doi.org/10.15252/embj.201694696
|
