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Cholesterol stimulates the lytic activity of Adenylate Cyclase Toxin on lipid membranes by promoting toxin oligomerization and formation of pores with a greater effective size
- Source :
- Addi. Archivo Digital para la Docencia y la Investigación, instname
- Publication Year :
- 2021
- Publisher :
- John Wiley & Sons, 2021.
-
Abstract
- Several toxins acting on animal cells present different, but specific, interactions with cholesterol. Bordetella pertussis infects the human respiratory tract and causes whooping cough, a highly contagious and resurgent disease. Its virulence factor adenylate cyclase toxin (ACT) plays an important role in the course of infection. ACT is a pore-forming cytolysin belonging to the Repeats in ToXin (RTX) family of leukotoxins/hemolysins and is capable of permeabilizing several cell types and lipid vesicles. Previously, we observed that in the presence of cholesterol ACT induces greater liposome permeabilization. Similarly, recent reports also implicate cholesterol in the cytotoxicity of an increasing number of pore-forming RTX toxins. However, the mechanistic details by which this sterol promotes the lytic activity of ACT or of these other RTX toxins remain largely unexplored and poorly understood. Here, we have applied a combination of biophysical techniques to dissect the role of cholesterol in pore formation by ACT. Our results indicate that cholesterol enhances the lytic potency of ACT by promoting toxin oligomerization, a step which is indispensable for ACT to accomplish membrane permeabilization and cell lysis. Since our experimental design eliminates the possibility that this cholesterol effect derives from toxin accumulation due to lateral lipid phase segregation, we hypothesize that cholesterol facilitates lytic pore formation, by favoring a toxin conformation more prone to protein-protein interactions and oligomerization. Our data shed light on the complex relationship between lipid membranes and protein toxins acting on these membranes. Coupling cholesterol binding, increased oligomerization and increased lytic activity is likely pertinent for other RTX cytolysins.<br />his study was supported by grants from the Spanish Ministerio de Economía y Competitividad BFU2017-82758-P (H.O.) and of Basque Government (Grupos Consolidados IT1264-19). D.G.B was recipients of a fellowship from the Bizkaia Biophysics Foundation, and JA was recipient of a fellowship from the Basque Government.
- Subjects :
- Bordetella pertussis
Cell Membrane Permeability
Bacterial toxins
Whooping Cough
bordetella-pertussis
Lipid Bilayers
translocation
Lipid-protein interactions
Microscopy, Atomic Force
Biochemistry
Virulence factor
cell biology
Adenylate cyclase
mechanisms
biology
Virulence
Chemistry
Cholesterol binding
unilamellar vesicles
Hemolysin
Cell biology
secretion
Cholesterol
Lytic cycle
Adenylate Cyclase Toxin
lipids (amino acids, peptides, and proteins)
pore-forming proteins
Porosity
adenylate cyclase
Protein Binding
Immunoblotting
lipid-protein interactions
Humans
Amino Acid Sequence
Molecular Biology
Unilamellar Liposomes
bacterial toxins
Perforin
Cell Membrane
biology.organism_classification
CyaA
Sterol
transport
identification
Cytolysin
Protein Multimerization
protein
Pore-forming proteins
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Addi. Archivo Digital para la Docencia y la Investigación, instname
- Accession number :
- edsair.doi.dedup.....3ae0567955638d001f969a5026d36776