Proapoptotic effects of P. aeruginosa involve inhibition of surfactant phosphatidylcholine synthesis

Abstract

Pseudomonas aeruginosa causes sepsis-induced acute lung injury, a disorder associated with deficiency of surfactant phosphatidylcholine (PtdCho). P. aeruginosa (PA103) utilizes a type III secretion system (TTSS) to induce programmed cell death. Herein, we observed that PA103 reduced alveolar PtdCho levels, resulting in impaired lung biophysical activity, an effect partly attributed to caspase-

CTP:phosphocholine cytidylyltransferase: Function, regulation, and structure of an amphitropic enzyme required for membrane biogenesis

“…Cleavage at this site in response to farnesol-induced apoptosis in CHO cells excluded CCTa from the nucleus but did not affect in vitro activity [185,218]. In contrast, caspase cleavage of CCTa in P. aeruginosa-infected murine lung epithelial cells was linked to decreased PC synthesis and apoptosis [219]. A more extensive analysis of inhibition of the CDP-choline pathway in apoptotic cells revealed that caspase 3 cleavage of CCTa is not required for inhibition of PC synthesis [218].…”

Surfactant and its role in the pathobiology of pulmonary infection

“…Mucoid strains also inhibit gene transcription of SP-B and SP-C, compounding surfactant deficiency that impairs stability of surfactant films [59]. In addition, other components of gram-negative bacteria, such as LPS inhibit phospholipid synthesis and secretion [59, 60]. Bacterial suppression of surfactant production may also be indirect via release of host cell cytokines, including tumor necrosis factor -α, which targets surfactant biosynthetic enzymes for degradation[57–60].…”

Calmodulin Binds and Stabilizes the Regulatory Enzyme, CTP:Phosphocholine Cytidylyltransferase

“…CCT␣ protein turnover might be a physiologically important control mechanism, since the enzyme is degraded by calciumactivated neutral proteinases (calpains) and death effector caspases (7)(8)(9). Calpain severs CCT␣ at the amino terminus and within the catalytic domain-membrane binding domain boundary (7).…”