The Cytocidal Spectrum of Bacillus thuringiensis Toxins: From Insects to Human Cancer Cells

Abstract

Bacillus thuringiensis (Bt) is a ubiquitous bacterium in soils, insect cadavers, phylloplane, water, and stored grain, that produces several proteins, each one toxic to different biological targets such as insects, nematodes, mites, protozoa, and mammalian cells. Most Bt toxins identify their particular target through the recognition of specific cell membrane receptors. Cry proteins are the best-known toxins from Bt and a great amount of research has been published. Cry are cytotoxic to insect larvae that affect important crops recognizing specific cell membrane receptors such as cadherin, aminopeptidase-N, and alkaline phosphatase. Furthermore, some Cry toxins such as Cry4A, Cry4B, and Cry11A act synergistically with Cyt toxins against dipteran larvae vectors of human disease. Research developed with Cry proteins revealed that these toxins also could kill human cancer cells through the interaction with specific receptors. Parasporins are a small group of patented toxins that may or may not have insecticidal activity. These proteins could kill a wide variety of mammalian cancer cells by recognizing specific membrane receptors, just like Cry toxins do. Surface layer proteins (SLP), unlike the other proteins produced by Bt, are also produced by most bacteria and archaebacteria. It was recently demonstrated that SLP produced by Bt could interact with membrane receptors of insect and human cancer cells to kill them. Cyt toxins have a structure that is mostly unrelated to Cry toxins; thereby, other mechanisms of action have been reported to them. These toxins affect mainly mosquitoes that are vectors of human diseases like Anopheles spp (malaria), Aedes spp (dengue, zika, and chikungunya), and Culex spp (Nile fever and Rift Valley fever), respectively. In addition to the Cry, Cyt, and parasporins toxins produced during spore formation as inclusion bodies, Bt strains also produce Vip (Vegetative insecticidal toxins) and Sip (Secreted insecticidal proteins) toxins with insecticidal activity during their vegetative growth phase.

Which Is Stronger? A Continuing Battle Between Cry Toxins and Insects

“…The middle domain II is also uncommon, as it is composed of three antiparallel β-sheets arranged in a circular mode to form a hydrophobic core with some highly variable and exposed loop regions ( Figure 1C ), which are often suggested to confer the binding specificity of the Cry toxin with the mid-intestinal epithelial cell membrane receptors of target insects ( Bravo et al, 2007 ; Evdokimov et al, 2014 ). Domain III, in contrast, forms a regular β-sandwich structure composed of two antiparallel β-sheets ( Figure 1D ; Palma et al, 2014 ; Xu et al, 2014 ), which typically participates in the specific binding with receptors such as N-acetylgalactosamine in the APN ( Bel et al, 2020 ), as well as in forming pores on the cell membranes ( Xu et al, 2014 ; Mendoza-Almanza et al, 2020 ). Besides, other domains in the protoxins may also participate in the stabilization of the various unique Cry toxin structures, in their selective dissolution and specific receptor recognition ( Palma et al, 2014 ).…”

“…Owing to their specificity and diversity, such toxins were also found to be environmentally friendly agents to kill Lepidoptera, Diptera, Coleoptera, and other target insects ( Fu et al, 2018 ). Therefore, Bt preparations are currently the most productive and widely used microbial insecticides in agriculture and forestry industries ( Mendoza-Almanza et al, 2020 ).…”

Baculovirus Expression and Functional Analysis of Vpa2 Proteins from Bacillus thuringiensis

“…Bacillus thuringiensis is an entomopathogenic bacterium that produces a diversity of insecticidal proteins, including vegetative pesticidal proteins that are secreted into the culture medium, rather than sequestered into the parasporal crystal like the many Cry and Cyt proteins produced by this bacterium during sporulation [15][16][17]. Vegetative pesticidal proteins are divided into three families (Vip, Vpa and Vpb) according to their pairwise percentage of amino acid identity and insecticidal specificities [18,19].…”

Bacillus thuringiensis Toxins: Functional Characterization and Mechanism of Action

“…The current knowledge about Vip proteins has also been reviewed [ 2 ], as has the contribution that the use of toxin mutants has made to the knowledge of the mode of action of the three-domain Cry proteins [ 3 ]. On the other hand, two more review papers recapitulate the information on the cytocidal activity of Bt proteins [ 4 ] or the insecticidal activity of Bt proteins against coleopteran pests [ 5 ]. All these review papers are of high value, allowing readers to stay updated on the different aspects of the Bt field described here.…”