An Introduction to the Toxins Special Issue on the Adenylate Cyclase Toxin

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the cytotoxicity of CyaA toxins against macrophages and showed that only CyaA from pertussis exhibits a cytotoxic activity against macrophages. Jakub Novak et al. and Helena Ostolaza et al. provide two complementary reviews describing the molecular basis of CyaA biogenesis and translocation. Novak and colleagues further highlight the diverse effects of CyaA on host phagocytes [5], while the Ostolaza group provides a detailed description of the potential molecular processes leading to CyaA translocation across the plasma membrane of target cells [6].
In a research article, Alexis Voegele and colleagues present new results on a membrane-active peptide derived from the CyaA translocation region, which is required for the delivery of the catalytic domain into host cytosol. They show that the arginine residues from the segment 454-484 from CyaA are involved in the successive steps of membrane interaction, folding, and permeabilization [7]. The authors propose that this region induces a local destabilization of the membrane, decreasing the energy required to translocate the catalytic domain across the plasma membrane.
Kurehong and collaborators report the effect on the pore-forming activity of point mutations of two residues (Q574 and E581) from the hydrophobic region of CyaA. They show that mutations to positively charged residues, which mimic the local positive valence as observed in hemolytic RTX proteins, increase the pore forming activity of CyaA [8]. Hence, compared to the efficiency of other bacterial hemolysins, the hemolytic activity of CyaA is rather low; however, this loss of hemolytic activity might be explained by the fact that the main functional property of CyaA is to intoxicate cells by translocating its catalytic domain into host cells and to induce a cascade of events disrupting host immune responses.
These last decades, intensive research activities have been dedicated to investigate the activation of the CyaA enzymatic domain. Recently, we showed that the catalytic domain contains a large region of structural disorder [9], and is poorly active in the absence of calmodulin, while calmodulin binding induces local folding, leading to the stabilization of the enzymatic core and the production of massive amounts of cAMP at the expense of ATP. Christian Johns and Natosha Finley report that the inactivation of calcium binding at Site 1 of calmodulin affects the stability of the N-terminal region of calmodulin and, consequently, its interaction with the catalytic domain of CyaA [10]. In the same topic, Thérèse Malliavin used molecular dynamics to highlight the contributions of several regions from both calmodulin and the CyaA catalytic domain to the formation of the active enzymatic complex [11].
Finally, Beyza Bulutoglu and Scott Banta review the works they have done using the C-terminal RTX domain of CyaA to engineer calcium-dependent nanotools they developed in the fields of bioseparation, hydrogel catalysis, and molecular recognition [12]. These applications are based on the remarkable properties of the RTX motifs, which are intrinsically disordered in the absence of calcium and undergo a disorder-to-order transition upon calcium binding [13,14].
Taken together, CyaA is intensively investigated to provide new insights into its intoxication process and how it disrupts host immune responses. As illustrated in the reviews and research articles of this Special Issue, methodologies from fundamental sciences applied to CyaA are crucial to provide a better understanding of the toxin and also to develop CyaA-based biotechnologies and vaccines.

Conflicts of Interest:
The author declares no conflict of interest.