4.6 Article

Paraoxonase 2 Serves a Proapopotic Function in Mouse and Human Cells in Response to the Pseudomonas aeruginosa Quorum-sensing Molecule N-(3-Oxododecanoyl)-homoserine Lactone

Journal

JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 11, Pages 7247-7258

Publisher

ELSEVIER
DOI: 10.1074/jbc.M114.620039

Keywords

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Funding

  1. National Institutes of Health [PN2-EY-018241, R01AM10141, K01CA106599, P20RR018733, R01 CA175003]
  2. Cystic Fibrosis Research, Inc.
  3. University of Louisville

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Pseudomonas aeruginosa use quorum-sensing molecules, including N-(3-oxododecanoyl)-homoserine lactone (C12), for intercellular communication. C12 activated apoptosis in mouse embryo fibroblasts (MEF) from both wild type (WT) and Bax/Bak double knock-out mice (WT MET and DKO MET that were responsive to C12, DKOR MEI): nuclei fragmented; mitochondrial membrane potential (Delta psi(mito)) depolarized; Ca2+ was released from the endoplasmic reticulum (ER), increasing cytosolic [Ca2+] (Ca-cyto); and caspase 3/7 was activated. DKOR MEF had been isolated from a nondonal pool of DKO MEE that were non-responsive to C12 (DKONR MEF). RNA seq analysis, quantitative PCR, and Western blots showed that WT and DKOR MEF both expressed genes associated with cancer, including paraoxonase 2 (PON2), whereas DKONR MEF expressed little PON2. Adenovirus-mediated expression of human PON2 in DKONR MEF rendered them responsive to C12: Delta psi(mito) depolarized, Ca-cyto increased, and caspase 3/7 activated. Human embryonic kidney 293T (HEK293T) cells expressed low levels of endogenous PON2, and these cells were also less responsive to C12. Overexpression of PON2, but not PON2-H114Q (no lactonase activity) in HEK293T cells caused them to become sensitive to C12. Because [C12] may reach high levels in biofilms in lungs of cystic fibrosis (CF) patients, PON2 lactonase activity may control Delta psi(mito), Ca2+ release from the ER, and apoptosis in CF airway epithelia. Coupled with previous data, these results also indicate that PON2 uses its lactonase activity to prevent Bax- and Bak-dependent apoptosis in response to common proapoptotic drugs like doxorubicin and staurosporine, but activates Bax- and Bak-independent apoptosis in response to C12.

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