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

Schwarzer, Christian; Fu, Zhu; Morita, Takeshi; Whitt, Aaron G.; Neely, Aaron M.; Li, Chi; Machen, Terry E.

doi:10.1074/jbc.m114.620039

Cited by 27 publications

(43 citation statements)

References 52 publications

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“…Recently, it was demonstrated that a relatively rapid, Յ2-h, induction of cytosolic Ca 2ϩ and of markers of apoptosis in mouse embryonic fibroblasts by 3OC12 was dependent upon PON2 hydrolytic activity (27). Such findings were counterintuitive as PON2 was thought to inactive 3OC12, and the PON2-dependent mechanism mediating these bioeffects could not be explained.…”

mentioning

confidence: 69%

“…Conversely, PON2 will promote p38, eIF2␣, and Ca 2ϩ signaling via intracellular acidification in response to 3OC12 exposure. Apoptotic responses to 3OC12 in mouse embryo fibroblasts were recently shown to depend upon PON2 hydrolytic activity (27). Thus, it appears that 3OC12-mediated apoptosis is driven by PON2-dependent intracellular acidification as well although further studies are needed to determine the contribution of PON2 to 3OC12-mediated apoptosis in different cell types.…”

Section: Discussionmentioning

confidence: 99%

“…In mouse embryonic fibroblasts, a [Ca 2ϩ ] c increase with 3OC12 treatment was shown to be dependent upon PON2 (27). We further explored the dependence of the [Ca 2ϩ ] c increase on PON2 in our PON2-expressing cell lines as well as in the HBEC transfected with PON2 siRNA.…”

Section: Pon2 Mediates Intracellular 3oc12 Acid Accumulationmentioning

confidence: 99%

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Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N -(3-Oxo-Dodecanoyl)- l -Homoserine Lactone

et al. 2015

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cPseudomonas aeruginosa produces N-(3-oxo-dodecanoyl)-L-homoserine lactone (3OC12), a crucial signaling molecule that elicits diverse biological responses in host cells thought to subvert immune defenses. The mechanism mediating many of these responses remains unknown. The intracellular lactonase paraoxonase 2 (PON2) hydrolyzes and inactivates 3OC12 and is therefore considered a component of host cells that attenuates 3OC12-mediated responses. Here, we demonstrate in cell lines and in primary human bronchial epithelial cells that 3OC12 is rapidly hydrolyzed intracellularly by PON2 to 3OC12 acid, which becomes trapped and accumulates within the cells. Subcellularly, 3OC12 acid accumulated within the mitochondria, a compartment where PON2 is localized. Treatment with 3OC12 caused a rapid PON2-dependent cytosolic and mitochondrial pH decrease, calcium release, and phosphorylation of stress signaling kinases. The results indicate a novel, PON2-dependent intracellular acidification mechanism by which 3OC12 can mediate its biological effects. Thus, PON2 is a central regulator of host cell responses to 3OC12, acting to decrease the availability of 3OC12 for receptor-mediated effects and acting to promote effects, such as calcium release and stress signaling, via intracellular acidification. P seudomonas aeruginosa is a common pathogen causing serious infections in immunocompromised and ill individuals due to the bacteria's ability to evade host immune responses and acquire antibiotic resistance (1). Many Gram-negative bacteria, including P. aeruginosa, produce acyl-homoserine lactone (AHL) signaling molecules which regulate the cell density-dependent expression of virulence factors in a process termed quorum sensing (QS) (1). The AHL N-(3-oxododecanoyl)-L-homoserine lactone (3OC12) is a key P. aeruginosa QS signal that has been shown to be necessary for biofilm maturation and full expression of virulence in P. aeruginosa animal infection models (2-5). Concentrations up to 600 M 3OC12 have been measured in P. aeruginosa biofilms in vitro (6). Concentrations of over 6 M 3OC12 have been detected in the sputum of individuals with pulmonary P. aeruginosa infections (7), suggesting active 3OC12 signaling in the human disease as well.In addition to modulating bacterial gene expression, 3OC12 elicits a multitude of biological responses in diverse mammalian cell types (8). Depending upon the cell type and dose, 3OC12 (10 to 100 M) can induce apoptosis, endoplasmic reticulum (ER) stress, chemotaxis, and proinflammatory gene expression (8-10). Conversely, 3OC12 inhibited lipopolysaccharide (LPS) induction of proinflammatory mediators in macrophages, fibroblasts, and epithelial cells and in vivo by repressing nuclear factor -light chain enhancer of activated B-cell (NF-B) signaling (11). In antigen-stimulated T-lymphocytes, 3OC12 inhibits cell proliferation and production of gamma interferon and interleukin-4 (IL-4), critical regulators of immunity (8,12). These diverse responses suggest that 3OC12 acts through multiple, and cell-...

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mentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

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Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N -(3-Oxo-Dodecanoyl)- l -Homoserine Lactone

et al. 2015

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“…Mounting data has shown that C12 is involved in the regulation of bacterial virulence genes and also interacts with eukaryotic cells (59,60). As a small, lipid-soluble and diffusible molecule, C12 readily enters cells of multiple tissues in the lungs of cystic fibrosis patients including fibroblasts, epithelial cells, leukocytes, and endothelial cells (9). Additionally C12 alters many aspects of eukaryotic cell physiology including the inhibition of the secretion of proinflammatory cytokines (61)(62)(63)(64), activation of p53, and inhibition of events commonly associated with cell death (65)(66)(67)(68).…”

Section: N-(3-oxododecanoyl)-homoserine Lactone (C12)mentioning

confidence: 99%

“…Previous studies indicate that C12 requires the lactonase / arylesterase PON2 to exert its cytotoxicity (8,9). …”

Section: Chapter 1: Introductionmentioning

confidence: 99%

Modulation of cell death signaling and cell proliferation by the interaction of homoserine lactones and Paraoxonase 2.

Neely¹

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Caspase‐1‐dependent mechanism mediating the harmful impacts of the quorum‐sensing molecule N‐(3‐oxo‐dodecanoyl)‐l‐homoserine lactone on the intestinal cells

Tao

Sun

Cai

et al. 2018

Journal Cellular Physiology

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N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12-HSL), a quorum-sensing (QS) molecule produced by Gram-negative bacteria in the gastrointestinal tract, adversly impacts host cells. Our previous study demonstrated that 3-oxo-C12-HSL induced a decrease in cell viability via cell apoptosis and eventually disrupted mucin synthesis from LS174T goblet cells. However, the molecular mechanism underlying cell apoptosis and whether pyroptosis was involved in this process are still unknown. In this study, we emphasized on the caspases signal pathway and sterile inflammation to reveal the harmful effects of 3-oxo-C12-HSL on LS174T goblet cells. Our data showed that 3-oxo-C12-HSL is a major inducer of oxidative stress indicated by a high level of intracellular reactive oxygen species (ROS). However, TQ416, an inhibitor of paraoxonase 2, can effectively block oxidative stress. A higher ROS level is the trigger for activating the caspase-1 and 3 cascade signal pathways. Blockade of ROS synthesis and caspase-1 and 3 cascades can obviously rescue the viability of LS174T cells after 3-oxo-C12-HSL treatment. We also found that paralleled with a higher level of ROS and caspases activation, an abnormal expression of proinflammatory cytokines was induced by 3-oxo-C12-HSL treatment; however, the blockage of TLRs-NF-κB pathway cannot restore cell viability and secretary function. These data collectively indicate that 3-oxo-C12-HSL exposure induces damages to cell viability and secretary function of LS174T goblet cells, which is mediated by oxidative stress, cell apoptosis, and sterile inflammation. Overall, the data in this study will provide a better understanding of the harmful impacts of some QS molecules on host cells and their underlying mechanism.

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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

Cited by 27 publications

References 52 publications

Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N -(3-Oxo-Dodecanoyl)- l -Homoserine Lactone

Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N -(3-Oxo-Dodecanoyl)- l -Homoserine Lactone

Modulation of cell death signaling and cell proliferation by the interaction of homoserine lactones and Paraoxonase 2.

Caspase‐1‐dependent mechanism mediating the harmful impacts of the quorum‐sensing molecule N‐(3‐oxo‐dodecanoyl)‐l‐homoserine lactone on the intestinal cells

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