9h5m

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

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]

References

1. ↑ 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
2. ↑ 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:http://dx.doi.org/10.1038/nature18590
3. ↑ 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
4. ↑ 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
5. ↑ 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
6. ↑ 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
7. ↑ 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
8. ↑ 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
9. ↑ 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:http://dx.doi.org/10.1038/nature18590
10. ↑ 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
11. ↑ 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
12. ↑ 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
13. ↑ 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
14. ↑ 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
15. ↑ 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
16. ↑ 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