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Breaking the chain at the membrane: paraoxonase 2 counteracts lipid peroxidation at the plasma membrane
Author(s) -
Hagmann Henning,
Kuczkowski Alexander,
Ruehl Michael,
Lamkemeyer Tobias,
Brodesser Susanne,
Horke Sven,
Dryer Stuart,
Schermer Bernhard,
Benzing Thomas,
Brinkkoetter Paul Thomas
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-240309
Subject(s) - lipid peroxidation , chemistry , extracellular , biochemistry , oxidative stress , microbiology and biotechnology , transmembrane protein , biology , receptor
Lipid peroxidation through electrophilic molecules of extracellular origin is involved in the pathogenesis of many inflammatory conditions. To counteract free radical actions at the plasma membrane, cells host a variety of antioxidative enzymes. Here we analyzed localization, membrane topology, and trafficking of PON2 a member of the paraoxonase family of 3 enzymatically active proteins (PON1–3) found to have antiatherogenic properties. Immunohistochemistry localized PON2 to the villous tip of human intestinal epithelial cells. Employing membrane preparations, surface biotinylation experiments, and mutational analyses in HEK 293T and HeLa cells, we demonstrate that PON2 is a type II transmembrane protein. A hydrophobic stretch in the N terminus was identified as single transmembrane domain of PON2. The enzymatically active domain faced the extracellular compartment, where it suppressed lipid peroxidation ( P <0.05) and regulated the glucosylceramide content, as demonstrated by mass spectrometry ( P <0.05). PON2 translocation to the plasma membrane was dependent on intracellular calcium responses and could be induced to >10‐fold as compared to baseline ( P =0.0001) by oxidative stress. Taken together, these data identify the paraoxonase protein PON2 as a type II transmembrane protein, which is dynamically translocated to the plasma membrane in response to oxidative stress to counteract lipid peroxidation.—Hagmann, H., Kuczkowski, A., Ruehl, M., Lamkemeyer, T., Brodesser, S., Horke, S., Dryer, S., Schermer, B., Benzing, T., Brinkkoetter, P. T. Breaking the chain at the membrane: paraoxonase 2 counteracts lipid peroxidation at the plasma membrane. FASEB J. 28, 28–1769 (1779). www.fasebj.org