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Intrinsic repair protects cells from pore-forming toxins by microvesicle shedding.
- Source :
-
Cell death and differentiation [Cell Death Differ] 2017 May; Vol. 24 (5), pp. 798-808. Date of Electronic Publication: 2017 Feb 10. - Publication Year :
- 2017
-
Abstract
- Pore-forming toxins (PFTs) are used by both the immune system and by pathogens to disrupt cell membranes. Cells attempt to repair this disruption in various ways, but the exact mechanism(s) that cells use are not fully understood, nor agreed upon. Current models for membrane repair include (1) patch formation (e.g., fusion of internal vesicles with plasma membrane defects), (2) endocytosis of the pores, and (3) shedding of the pores by blebbing from the cell membrane. In this study, we sought to determine the specific mechanism(s) that cells use to resist three different cholesterol-dependent PFTs: Streptolysin O, Perfringolysin O, and Intermedilysin. We found that all three toxins were shed from cells by blebbing from the cell membrane on extracellular microvesicles (MVs). Unique among the cells studied, we found that macrophages were 10 times more resistant to the toxins, yet they shed significantly smaller vesicles than the other cells. To examine the mechanism of shedding, we tested whether toxins with engineered defects in pore formation or oligomerization were shed. We found that oligomerization was necessary and sufficient for membrane shedding, suggesting that calcium influx and patch formation were not required for shedding. However, pore formation enhanced shedding, suggesting that calcium influx and patch formation enhance repair. In contrast, monomeric toxins were endocytosed. These data indicate that cells use two interrelated mechanisms of membrane repair: lipid-dependent MV shedding, which we term 'intrinsic repair', and patch formation by intracellular organelles. Endocytosis may act after membrane repair is complete by removing inactivated and monomeric toxins from the cell surface.
- Subjects :
- Animals
Bacterial Proteins chemistry
Bacterial Proteins pharmacology
Bacterial Toxins chemistry
Bacteriocins chemistry
Bacteriocins pharmacology
Calcium metabolism
Cell Membrane chemistry
Cell Membrane metabolism
Cell-Derived Microparticles chemistry
Cell-Derived Microparticles metabolism
Endocytosis
Female
HEK293 Cells
HeLa Cells
Hemolysin Proteins chemistry
Hemolysin Proteins pharmacology
Humans
Macrophages cytology
Macrophages metabolism
Male
Mice
Mice, Inbred C57BL
Mutation
Primary Cell Culture
Protein Engineering
Protein Multimerization
Recombinant Proteins chemistry
Recombinant Proteins pharmacology
Streptolysins chemistry
Streptolysins pharmacology
THP-1 Cells
Bacterial Toxins pharmacology
Cell Membrane drug effects
Cell Membrane Permeability drug effects
Cell-Derived Microparticles drug effects
Macrophages drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5403
- Volume :
- 24
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell death and differentiation
- Publication Type :
- Academic Journal
- Accession number :
- 28186501
- Full Text :
- https://doi.org/10.1038/cdd.2017.11