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Journal of Lipid Research, Vol. 47, 2314-2324, October 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

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

Florita C. Henderson^1,*,**, Olga L. Miakotina^1,*,** and Rama K. Mallampalli^2,*,,,**

^* Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242
Department of Biochemistry, The University of Iowa, Iowa City, IA 52242
The Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, IA 52242
^** Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242

Published, JLR Papers in Press, July 25, 2006.

¹ F. C. Henderson and O. L. Miakotina contributed equally to this work.

² To whom correspondence should be addressed. e-mail: rama-mallampalli{at}uiowa.edu

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-dependent cleavage of the key PtdCho biosynthetic enzyme, CTP:phosphocholine cytidylyltransferase- (CCT). Expression of recombinant CCT variants harboring point mutations at putative caspase cleavage sites in murine lung epithelia resulted in partial proteolytic resistance of CCT to PA103. Further, caspase-directed CCT degradation, decreased PtdCho levels, and cell death in murine lung epithelia were lessened after exposure of cells to bacterial strains lacking the TTSS gene product, exotoxin U (ExoU), but not ExoT. These observations suggest that during the proapoptotic program driven by P. aeruginosa, deleterious effects on phospholipid metabolism are mediated by a TTSS in concert with caspase activation, resulting in proteolysis of a key surfactant biosynthetic enzyme.

Supplementary key words apoptosis • caspase • Pseudomonas

Abbreviations: CCT, CTP:phosphocholine cytidylyltransferase; CPT, cholinephosphotransferase; DPPC, dipalmitoylphosphatidylcholine; Exo, exotoxin; LDH, lactate dehydrogenase; PARP, poly (ADP-ribose) polymerase; PtdCho, phosphatidylcholine; TTSS, type III secretion system

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