title: 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.
abstract: 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 MEF and DKO MEF that were responsive to C12, DKOR MEF): nuclei fragmented; mitochondrial membrane potential (Δψmito) depolarized; Ca(2+) was released from the endoplasmic reticulum (ER), increasing cytosolic [Ca(2+)] (Cacyto); and caspase 3/7 was activated. DKOR MEF had been isolated from a nonclonal pool of DKO MEF that were non-responsive to C12 (DKONR MEF). RNAseq 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: Δψmito depolarized, Cacyto 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 Δψmito, Ca(2+) 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.
authors: From the Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720-3200 and.
authors: Christian
authors: C
authors: Schwarzer
authors: From the Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720-3200 and.
authors: Zhu
authors: Z
authors: Fu
authors: From the Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720-3200 and.
authors: Takeshi
authors: T
authors: Morita
authors: the Departments of Medicine, Pharmacology, and Toxicology, Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202.
authors: Aaron G
authors: AG
authors: Whitt
authors: the Departments of Medicine, Pharmacology, and Toxicology, Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202.
authors: Aaron M
authors: AM
authors: Neely
authors: the Departments of Medicine, Pharmacology, and Toxicology, Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202.
authors: Chi
authors: C
authors: Li
authors: From the Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720-3200 and tmachen@berkeley.edu.
authors: Terry E
authors: TE
authors: Machen
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D043303:Aryldialkylphosphatase / Q000378:metabolism*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006714:Homoserine / Q000031:analogs & derivatives* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D011552:Pseudomonas Infections / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D053038:Quorum Sensing
chemical_list: C109860:N-(3-oxododecanoyl)homoserine lactone; D006714:Homoserine; C578990:PON2 protein, mouse; D043303:Aryldialkylphosphatase; C468411:PON2 protein, human; D015107:4-Butyrolactone
keywords: Apoptosis; Bax; Cancer; Paraoxonase 2; Pseudomonas aeruginosa (P. aeruginosa); Quorum Sensing
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