5tj4

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). The different isoforms recognize and bind different phospholipids on membranes, promoting cell death of different target cells (PubMed:34022140, PubMed:36157507).^{[3] [4] [5] [6]} Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death and mediates pyroptosis of host human cells (PubMed:28154144, PubMed:36157507). 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). 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).^{[7] [8]} 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 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).^[9]

See Also

• Gasdermin 3D structures

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. ↑ 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
8. ↑ 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
9. ↑ 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
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