Cytotoxic properties and medical usages of Cyt toxins from Bacillus thuringiensis subsp. israelensis

Bacillus thuringiensis subsp. israelensis (Bti) is a Gram-positive spore-forming bacterium and a highly potent mosquitocidal strain. During the sporulation phase it synthetizes several pore-forming pro-S-endotoxins: four of the Cry (Crystal) family (Cry4Aa, Cry4Ba, Cry10Aa and Cry11Aa) and three of the Cyt (Cytotoxic) family (Cyt1Aa and a tiny amount of Cyt2Ba and Cyt1Ca). These proteins are assembled together into a crystalline-like body which is dissolved in the alkaline environment of the larval midgut, digested and activated by endoproteases. Cry pro-toxins are composed of three domains. One domain is associated with a specific receptor on the midgut epithelial cells and the other domains undergo conformational change and are inserted into the lipid bilayer. Once a number of these toxins are associated together within the membrane, they create pores that interrupt the osmotic balance of the cells and lead to cell destruction. The Cyt pro-toxins have only one domain which non-specifically destroys various insect and mammalian cells by a pore-forming or a detergent-like mechanism of membrane lysis. Several studies have shown that Cyt toxins serve as receptors for the Crys (e.g., Cry11Aa). They act synergistically to increase the toxicity of Cry toxins and also prevent the development of larval resistance to Crys. We have recently crystallized and deciphered the 3D structure of the active form of Cyt1Aa and CytBa toxins and demonstrated their similar spatial structure and homology to other pore-forming toxins such as Cyt2Aa, volvatoxin A2 (VVA2) and the Erwinia virulence factor (Evf). This chapter summarizes up-to-date findings on the Cyts family and their homology toxins and discusses the potential use of these toxins in the therapeutic field, especially by specific targeting of Cyts to cancer cells.