Calpain-Mediated Processing of Adenylate Cyclase Toxin Generates a Cytosolic Soluble Catalytically Active N-Terminal Domain

Bordetella pertussis, the whooping cough pathogen, secretes several virulence factors among which adenylate cyclase toxin (ACT) is essential for establishment of the disease in the respiratory tract. ACT weakens host defenses by suppressing important bactericidal activities of the phagocytic cells. Up to now, it was believed that cell intoxication by ACT was a consequence of the accumulation of abnormally high levels of cAMP, generated exclusively beneath the host plasma membrane by the toxin N-terminal catalytic adenylate cyclase (AC) domain, upon its direct translocation across the lipid bilayer. Here we show that host calpain, a calcium-dependent Cys-protease, is activated into the phagocytes by a toxin-triggered calcium rise, resulting in the proteolytic cleavage of the toxin N-terminal domain that releases a catalytically active "soluble AC''. The calpain-mediated ACT processing allows trafficking of the "soluble AC'' domain into subcellular organella. At least two strategic advantages arise from this singular toxin cleavage, enhancing the specificity of action, and simultaneously preventing an indiscriminate activation of cAMP effectors throughout the cell. The present study provides novel insights into the toxin mechanism of action, as the calpain-mediated toxin processing would confer ACT the capacity for a space- and time-coordinated production of different cAMP "pools'', which would play different roles in the cell pathophysiology.

Whales and Sonar: Environmental Exemptions for the Navy's Mid-Frequency Active Sonar Training.

Mid-frequency active (MFA) sonar emits pulses of sound from an underwater transmitter to help determine the size, distance, and speed of objects. The sound waves bounce off objects and reflect back to underwater acoustic receivers as an echo. MFA sonar has been used since World War II, and the Navy indicates it is the only reliable way to track submarines, especially more recently designed submarines that operate more quietly, making them more difficult to detect. Scientists have asserted that sonar may harm certain marine mammals under certain conditions, especially beaked whales. Depending on the exposure, they believe that sonar may damage the ears of the mammals, causing hemorrhaging and/or disorientation. The Navy agrees that the sonar may harm some marine mammals, but says it has taken protective measures so that animals are not harmed. (PDF contains 20 pages)