Michel-Robert Popoff (PI), Institut Pasteur, Paris France
Clostridial pore-forming toxins, powerful virulence factors
Pore formation through the plasma membrane is a common mechanism of activity of many clostridial toxins. More than one third of clostridial toxins are pore-forming toxins (PFTs). they belong to the super family of beta-PFTs, and they retain conserved structural domains including a receptor-binding domain, one or two domains involved in oligomerization, and a domain containing alpha-helices which unfold forming amphipathic beta-sheets. Beta-PFTs are released by the clostridia as water-soluble monomers, which bind to host cell surface receptors and oligomerize into ring-like structure (prepore). A subsequent conformational change results in the unfolding of an amphipatic beta-barrel, which inserts into the membrane leading to the formation of hydrophilic pores of various sizes according to the toxin. Cholesterol-dependent cytolysins, the prototype of which being the Clostridium perfringens perfringolysin (PFO), form large pores, whereas beta-PFTs from the aerolysin family such as C. perfringens epsilon toxin (ETX) and C. septicum alpha toxin, induce small pores. A third clostridial PFT class consists of beta-PFTs such as C. perfringens delta toxin and NetB, which are structurally related to Staphylococcus aureus alpha toxin. Clostridial beta-PFTs are involved in various diseases such as gangrene, enteritis, and necrotic enteritis. Notably ETX is a potent toxin which is able to cross the blood-brain barrier and to target specific neurons and oligodendrocytes in the brain leading to release of glutamate and neurological symptoms of excitation and rapid death. Epsilon toxin causes slightly anion selective pores leading to a rapid loss of intracellular K+ and to a Na+ entry, which are accompanied by a rapid ATP depletion. Epsilon toxin induces a permeabilization of mitochondrial membranes leading to the release of cytochrome c as well as a mitochondrial-nuclear translocation of apoptosis-inducing factor, which is a caspase-independent cell death factor. However, cell death results from a necrotic process and not from apoptosis. ETX induces a demyelination and could be involved in neurodegenerative diseases in man such as multiple sclerosis. Interestingly, the binding component of clostridial binary toxins are beta-pore-forming proteins which are related to beta-PFTs and which selectively mediate the internalization of the enzymatic components. This suggests that beta-PFTs have emerged from a common ancestor and that they have been spread in various clostridia, as well as in other microorganisms and eukaryotes.
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Further information by:
Prof. Dr. Roland Benz, Professor of Biotechnology - Focus Area: Health - Life Sciences & Chemistry - Email: r.benz [at] jacobs-university.de - Tel: +49 421 200-3151 - Link to Homepage: https://www.jacobs-university.de/ses/rbenz