8et1

Structural highlights

Function

GSDMB_HUMAN Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death (PubMed:32299851). This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-B, N-terminal) binds to membranes and forms pores, triggering pyroptosis (PubMed:32299851). Also acts as a regulator of epithelial cell repair independently of programmed cell death: translocates to the plasma membrane and promotes epithelial maintenance and repair by regulating PTK2/FAK-mediated phosphorylation of PDGFA (PubMed:35021065).^{[1] [2]} Pore-forming protein produced by cleavage by granzyme A (GZMA), which causes membrane permeabilization and pyroptosis in target cells of cytotoxic T and natural killer (NK) cells (PubMed:27281216, PubMed:32299851). Key downstream mediator of granzyme-mediated cell death: (1) granzyme A (GZMA), delivered to target cells from cytotoxic T- and NK-cells, (2) specifically cleaves Gasdermin-B to generate this form (PubMed:32299851). After cleavage, moves to the plasma membrane, homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (PubMed:32299851, PubMed:36599845, PubMed:36991122, PubMed:36991125). The different isoforms recognize and bind different phospholipids on membranes, promoting cell death of different target cells (PubMed:34022140, PubMed:36157507, PubMed:36991122, PubMed:36991125).^{[3] [4] [5] [6] [7] [8] [9]} Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death and mediates pyroptosis (PubMed:28154144, PubMed:36157507, PubMed:36899106, PubMed:36991122, PubMed:36991125). Following cleavage and activation by granzyme A (GZMA), the N-terminal part binds to membrane inner leaflet lipids, homooligomerizes within the human plasma membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (PubMed:28154144, PubMed:36157507, PubMed:36899106, PubMed:36991122, PubMed:36991125). Recognizes and binds membrane inner leaflet lipids of human cells, such as phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate, and more weakly to phosphatidic acid (PubMed:28154144, PubMed:36157507). Also binds sufatide, a component of the apical membrane of epithelial cells (PubMed:28154144).^{[10] [11] [12] [13] [14]} Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death and mediates pyroptosis of human cells (PubMed:36899106, PubMed:36991122, PubMed:36991125). Following cleavage and activation by granzyme A (GZMA), the N-terminal part binds to membrane inner leaflet lipids, homooligomerizes within the human plasma membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (PubMed:36899106, PubMed:36991122, PubMed:36991125).^{[15] [16] [17]} Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death and specifically mediates cell death of Gram-negative bacteria in response to infection (PubMed:34022140). Following cleavage and activation by granzyme A (GZMA), the N-terminal part recognizes and binds phospholipids found on Gram-negative bacterial membranes, such as lipid A and cariolipin, homooligomerizes within the bacterial membranes and forms pores, triggering pyroptosis followed by cell death (PubMed:34022140). In contrast to isoform 4, does not bind to membrane inner leaflet lipids of host human cell, such as phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate (PubMed:34022140).^[18] Not able to trigger pyroptosis.^{[19] [20] [21]} Not able to trigger pyroptosis.^{[22] [23] [24]}

References

1. ↑ Zhou Z, He H, Wang K, Shi X, Wang Y, Su Y, Wang Y, Li D, Liu W, Zhang Y, Shen L, Han W, Shen L, Ding J, Shao F. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science. 2020 May 29;368(6494):eaaz7548. PMID:32299851 doi:10.1126/science.aaz7548
2. ↑ Rana N, Privitera G, Kondolf HC, Bulek K, Lechuga S, De Salvo C, Corridoni D, Antanaviciute A, Maywald RL, Hurtado AM, Zhao J, Huang EH, Li X, Chan ER, Simmons A, Bamias G, Abbott DW, Heaney JD, Ivanov AI, Pizarro TT. GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis. Cell. 2022 Jan 20;185(2):283-298.e17. PMID:35021065 doi:10.1016/j.cell.2021.12.024
3. ↑ 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
4. ↑ Zhou Z, He H, Wang K, Shi X, Wang Y, Su Y, Wang Y, Li D, Liu W, Zhang Y, Shen L, Han W, Shen L, Ding J, Shao F. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science. 2020 May 29;368(6494):eaaz7548. PMID:32299851 doi:10.1126/science.aaz7548
5. ↑ Hansen JM, de Jong MF, Wu Q, Zhang LS, Heisler DB, Alto LT, Alto NM. Pathogenic ubiquitination of GSDMB inhibits NK cell bactericidal functions. Cell. 2021 Jun 10;184(12):3178-3191.e18. PMID:34022140 doi:10.1016/j.cell.2021.04.036
6. ↑ Gong W, Liu P, Liu J, Li Y, Zheng T, Wu X, Zhao Y, Ren J. GSDMB N-terminal assembles in plasma membrane to execute pyroptotic cell death. Genes Dis. 2022 Feb 8;9(6):1405-1407. PMID:36157507 doi:10.1016/j.gendis.2021.12.022
7. ↑ Yin H, Zheng J, He Q, Zhang X, Li X, Ma Y, Liang X, Gao J, Kocsis BL, Li Z, Liu X, Alto NM, Li L, Zhang H. Insights into the GSDMB-mediated cellular lysis and its targeting by IpaH7.8. Nat Commun. 2023 Jan 4;14(1):61. PMID:36599845 doi:10.1038/s41467-022-35725-0
8. ↑ Wang C, Shivcharan S, Tian T, Wright S, Ma D, Chang J, Li K, Song K, Xu C, Rathinam VA, Ruan J. Structural basis for GSDMB pore formation and its targeting by IpaH7.8. Nature. 2023 Apr;616(7957):590-597. PMID:36991122 doi:10.1038/s41586-023-05832-z
9. ↑ Zhong X, Zeng H, Zhou Z, Su Y, Cheng H, Hou Y, She Y, Feng N, Wang J, Shao F, Ding J. Structural mechanisms for regulation of GSDMB pore-forming activity. Nature. 2023 Mar 29. PMID:36991125 doi:10.1038/s41586-023-05872-5
10. ↑ Chao KL, Kulakova L, Herzberg O. Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein. Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):E1128-E1137. doi:, 10.1073/pnas.1616783114. Epub 2017 Feb 1. PMID:28154144 doi:http://dx.doi.org/10.1073/pnas.1616783114
11. ↑ Gong W, Liu P, Liu J, Li Y, Zheng T, Wu X, Zhao Y, Ren J. GSDMB N-terminal assembles in plasma membrane to execute pyroptotic cell death. Genes Dis. 2022 Feb 8;9(6):1405-1407. PMID:36157507 doi:10.1016/j.gendis.2021.12.022
12. ↑ Oltra SS, Colomo S, Sin L, Pérez-López M, Lázaro S, Molina-Crespo A, Choi KH, Ros-Pardo D, Martínez L, Morales S, González-Paramos C, Orantes A, Soriano M, Hernández A, Lluch A, Rojo F, Albanell J, Gómez-Puertas P, Ko JK, Sarrió D, Moreno-Bueno G. Distinct GSDMB protein isoforms and protease cleavage processes differentially control pyroptotic cell death and mitochondrial damage in cancer cells. Cell Death Differ. 2023 May;30(5):1366-1381. PMID:36899106 doi:10.1038/s41418-023-01143-y
13. ↑ Wang C, Shivcharan S, Tian T, Wright S, Ma D, Chang J, Li K, Song K, Xu C, Rathinam VA, Ruan J. Structural basis for GSDMB pore formation and its targeting by IpaH7.8. Nature. 2023 Apr;616(7957):590-597. PMID:36991122 doi:10.1038/s41586-023-05832-z
14. ↑ Zhong X, Zeng H, Zhou Z, Su Y, Cheng H, Hou Y, She Y, Feng N, Wang J, Shao F, Ding J. Structural mechanisms for regulation of GSDMB pore-forming activity. Nature. 2023 Mar 29. PMID:36991125 doi:10.1038/s41586-023-05872-5
15. ↑ Oltra SS, Colomo S, Sin L, Pérez-López M, Lázaro S, Molina-Crespo A, Choi KH, Ros-Pardo D, Martínez L, Morales S, González-Paramos C, Orantes A, Soriano M, Hernández A, Lluch A, Rojo F, Albanell J, Gómez-Puertas P, Ko JK, Sarrió D, Moreno-Bueno G. Distinct GSDMB protein isoforms and protease cleavage processes differentially control pyroptotic cell death and mitochondrial damage in cancer cells. Cell Death Differ. 2023 May;30(5):1366-1381. PMID:36899106 doi:10.1038/s41418-023-01143-y
16. ↑ Wang C, Shivcharan S, Tian T, Wright S, Ma D, Chang J, Li K, Song K, Xu C, Rathinam VA, Ruan J. Structural basis for GSDMB pore formation and its targeting by IpaH7.8. Nature. 2023 Apr;616(7957):590-597. PMID:36991122 doi:10.1038/s41586-023-05832-z
17. ↑ Zhong X, Zeng H, Zhou Z, Su Y, Cheng H, Hou Y, She Y, Feng N, Wang J, Shao F, Ding J. Structural mechanisms for regulation of GSDMB pore-forming activity. Nature. 2023 Mar 29. PMID:36991125 doi:10.1038/s41586-023-05872-5
18. ↑ Hansen JM, de Jong MF, Wu Q, Zhang LS, Heisler DB, Alto LT, Alto NM. Pathogenic ubiquitination of GSDMB inhibits NK cell bactericidal functions. Cell. 2021 Jun 10;184(12):3178-3191.e18. PMID:34022140 doi:10.1016/j.cell.2021.04.036
19. ↑ Oltra SS, Colomo S, Sin L, Pérez-López M, Lázaro S, Molina-Crespo A, Choi KH, Ros-Pardo D, Martínez L, Morales S, González-Paramos C, Orantes A, Soriano M, Hernández A, Lluch A, Rojo F, Albanell J, Gómez-Puertas P, Ko JK, Sarrió D, Moreno-Bueno G. Distinct GSDMB protein isoforms and protease cleavage processes differentially control pyroptotic cell death and mitochondrial damage in cancer cells. Cell Death Differ. 2023 May;30(5):1366-1381. PMID:36899106 doi:10.1038/s41418-023-01143-y
20. ↑ Wang C, Shivcharan S, Tian T, Wright S, Ma D, Chang J, Li K, Song K, Xu C, Rathinam VA, Ruan J. Structural basis for GSDMB pore formation and its targeting by IpaH7.8. Nature. 2023 Apr;616(7957):590-597. PMID:36991122 doi:10.1038/s41586-023-05832-z
21. ↑ Zhong X, Zeng H, Zhou Z, Su Y, Cheng H, Hou Y, She Y, Feng N, Wang J, Shao F, Ding J. Structural mechanisms for regulation of GSDMB pore-forming activity. Nature. 2023 Mar 29. PMID:36991125 doi:10.1038/s41586-023-05872-5
22. ↑ Oltra SS, Colomo S, Sin L, Pérez-López M, Lázaro S, Molina-Crespo A, Choi KH, Ros-Pardo D, Martínez L, Morales S, González-Paramos C, Orantes A, Soriano M, Hernández A, Lluch A, Rojo F, Albanell J, Gómez-Puertas P, Ko JK, Sarrió D, Moreno-Bueno G. Distinct GSDMB protein isoforms and protease cleavage processes differentially control pyroptotic cell death and mitochondrial damage in cancer cells. Cell Death Differ. 2023 May;30(5):1366-1381. PMID:36899106 doi:10.1038/s41418-023-01143-y
23. ↑ Wang C, Shivcharan S, Tian T, Wright S, Ma D, Chang J, Li K, Song K, Xu C, Rathinam VA, Ruan J. Structural basis for GSDMB pore formation and its targeting by IpaH7.8. Nature. 2023 Apr;616(7957):590-597. PMID:36991122 doi:10.1038/s41586-023-05832-z
24. ↑ Zhong X, Zeng H, Zhou Z, Su Y, Cheng H, Hou Y, She Y, Feng N, Wang J, Shao F, Ding J. Structural mechanisms for regulation of GSDMB pore-forming activity. Nature. 2023 Mar 29. PMID:36991125 doi:10.1038/s41586-023-05872-5