Pore-forming Proteins As Drivers of Membrane Permeabilization in Cell Death Pathways

Overview

Journal Nat Rev Mol Cell Biol

Specialties Cell Biology
Molecular Biology

Date 2022 Dec 21

PMID 36543934

Authors

Peter Vandenabeele

Geert Bultynck

Savvas N Savvides

Affiliations

Soon will be listed here.

Abstract

Regulated cell death (RCD) relies on activation and recruitment of pore-forming proteins (PFPs) that function as executioners of specific cell death pathways: apoptosis regulator BAX (BAX), BCL-2 homologous antagonist/killer (BAK) and BCL-2-related ovarian killer protein (BOK) for apoptosis, gasdermins (GSDMs) for pyroptosis and mixed lineage kinase domain-like protein (MLKL) for necroptosis. Inactive precursors of PFPs are converted into pore-forming entities through activation, membrane recruitment, membrane insertion and oligomerization. These mechanisms involve protein-protein and protein-lipid interactions, proteolytic processing and phosphorylation. In this Review, we discuss the structural rearrangements incurred by RCD-related PFPs and describe the mechanisms that manifest conversion from autoinhibited to membrane-embedded molecular states. We further discuss the formation and maturation of membrane pores formed by BAX/BAK/BOK, GSDMs and MLKL, leading to diverse pore architectures. Lastly, we highlight commonalities and differences of PFP mechanisms involving BAX/BAK/BOK, GSDMs and MLKL and conclude with a discussion on how, in a population of challenged cells, the coexistence of cell death modalities may have profound physiological and pathophysiological implications.

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References

Ameisen J . Looking for death at the core of life in the light of evolution. Cell Death Differ. 2003; 11(1):4-10. DOI: 10.1038/sj.cdd.4401356. View

Vriz S, Reiter S, Galliot B . Cell death: a program to regenerate. Curr Top Dev Biol. 2014; 108:121-51. DOI: 10.1016/B978-0-12-391498-9.00002-4. View

Fuchs Y, Steller H . Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat Rev Mol Cell Biol. 2015; 16(6):329-44. PMC: 4511109. DOI: 10.1038/nrm3999. View

Harayama T, Riezman H . Understanding the diversity of membrane lipid composition. Nat Rev Mol Cell Biol. 2018; 19(5):281-296. DOI: 10.1038/nrm.2017.138. View

Liu X, Lieberman J . Knocking 'em Dead: Pore-Forming Proteins in Immune Defense. Annu Rev Immunol. 2020; 38:455-485. PMC: 7260445. DOI: 10.1146/annurev-immunol-111319-023800. View

Tsujimoto Y . Apoptosis and necrosis: intracellular ATP level as a determinant for cell death modes. Cell Death Differ. 1997; 4(6):429-34. DOI: 10.1038/sj.cdd.4400262. View

Cai Z, Jitkaew S, Zhao J, Chiang H, Choksi S, Liu J . Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat Cell Biol. 2013; 16(1):55-65. PMC: 8369836. DOI: 10.1038/ncb2883. View

Xia B, Fang S, Chen X, Hu H, Chen P, Wang H . MLKL forms cation channels. Cell Res. 2016; 26(5):517-28. PMC: 4856759. DOI: 10.1038/cr.2016.26. View

Ammendolia D, Bement W, Brumell J . Plasma membrane integrity: implications for health and disease. BMC Biol. 2021; 19(1):71. PMC: 8042475. DOI: 10.1186/s12915-021-00972-y. View

10.

Green D . The Mitochondrial Pathway of Apoptosis: Part I: MOMP and Beyond. Cold Spring Harb Perspect Biol. 2022; 14(5). PMC: 9159267. DOI: 10.1101/cshperspect.a041038. View

11.

Kale J, Osterlund E, Andrews D . BCL-2 family proteins: changing partners in the dance towards death. Cell Death Differ. 2017; 25(1):65-80. PMC: 5729540. DOI: 10.1038/cdd.2017.186. View

12.

Singh R, Letai A, Sarosiek K . Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol. 2019; 20(3):175-193. PMC: 7325303. DOI: 10.1038/s41580-018-0089-8. View

13.

Wei M, Zong W, Cheng E, LINDSTEN T, Panoutsakopoulou V, Ross A . Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 2001; 292(5517):727-30. PMC: 3049805. DOI: 10.1126/science.1059108. View

14.

Tait S, Green D . Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 2010; 11(9):621-32. DOI: 10.1038/nrm2952. View

15.

Llambi F, Wang Y, Victor B, Yang M, Schneider D, Gingras S . BOK Is a Non-canonical BCL-2 Family Effector of Apoptosis Regulated by ER-Associated Degradation. Cell. 2016; 165(2):421-33. PMC: 5018360. DOI: 10.1016/j.cell.2016.02.026. View

16.

Shalaby R, Diwan A, Flores-Romero H, Hertlein V, Garcia-Saez A . Visualization of BOK pores independent of BAX and BAK reveals a similar mechanism with differing regulation. Cell Death Differ. 2022; 30(3):731-741. PMC: 9607731. DOI: 10.1038/s41418-022-01078-w. View

17.

Flores-Romero H, Hohorst L, John M, Albert M, King L, Beckmann L . BCL-2-family protein tBID can act as a BAX-like effector of apoptosis. EMBO J. 2021; 41(2):e108690. PMC: 8762556. DOI: 10.15252/embj.2021108690. View

18.

Shalaby R, Flores-Romero H, Garcia-Saez A . The Mysteries around the BCL-2 Family Member BOK. Biomolecules. 2020; 10(12). PMC: 7762061. DOI: 10.3390/biom10121638. View

19.

Flores-Romero H, Ros U, Garcia-Saez A . Pore formation in regulated cell death. EMBO J. 2020; 39(23):e105753. PMC: 7705454. DOI: 10.15252/embj.2020105753. View

20.

Cosentino K, Hertlein V, Jenner A, Dellmann T, Gojkovic M, Pena-Blanco A . The interplay between BAX and BAK tunes apoptotic pore growth to control mitochondrial-DNA-mediated inflammation. Mol Cell. 2022; 82(5):933-949.e9. PMC: 8901441. DOI: 10.1016/j.molcel.2022.01.008. View