A novel role for 12/15-lipoxygenase in regulating autophagy.
A novel role for 12/15-lipoxygenase in regulating autophagy.
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DOI：
10.1016/j.redox.2014.11.005
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发表时间：
2015
期刊：
影响因子：
11.4
通讯作者：
O'Donnell, Valerie B.
中科院分区：
文献类型：
--
作者：
Morgan, Alwena H.;Hammond, Victoria J.;Sakoh-Nakatogawa, Machiko;Ohsumi, Yoshinori;Thomas, Christopher P.;Blanchet, Fabien;Piguet, Vincent;Kiselyov, Kirill;O'Donnell, Valerie B.
12/15-脂氧合酶（LOX）在单核细胞和巨噬细胞中酶促产生氧化磷脂。在此，我们表明，在12/15-LOX缺陷的细胞含有缺陷的线粒体和许多细胞质空泡含有电子致密材料，表明在自噬或膜加工缺陷，然而，LC 3的表达和脂质化都是正常的基础和氯喹治疗。发现LOX衍生的氧化磷脂，12-羟基二十碳四烯酸-磷脂酰乙醇胺（12-HETE-PE）是酵母Atg 8脂化的优选底物，而天然PE和氧化PE都是LC 3脂化的有效底物。最后，磷脂组学证明了几种磷脂类的水平改变。因此，我们表明，12/15-LOX产生的氧化磷脂可以作为有效自噬所需的关键蛋白质的底物，这种酶缺乏的细胞显示自噬功能障碍的证据。这些数据首次将磷脂氧化与自噬功能联系起来。12/15-脂氧合酶缺陷型巨噬细胞显示自噬功能障碍的证据。12-HETE-PE是LC 2和Atg 8脂化的底物。缺乏12/15-脂氧合酶的巨噬细胞显示磷脂含量改变。
12/15-Lipoxygenase (LOX) enzymatically generates oxidized phospholipids in monocytes and macrophages. Herein, we show that cells deficient in 12/15-LOX contain defective mitochondria and numerous cytoplasmic vacuoles containing electron dense material, indicating defects in autophagy or membrane processing, However, both LC3 expression and lipidation were normal both basally and on chloroquine treatment. A LOX-derived oxidized phospholipid, 12-hydroxyeicosatetraenoic acid-phosphatidylethanolamine (12-HETE-PE) was found to be a preferred substrate for yeast Atg8 lipidation, versus native PE, while both native and oxidized PE were effective substrates for LC3 lipidation. Last, phospholipidomics demonstrated altered levels of several phospholipid classes. Thus, we show that oxidized phospholipids generated by 12/15-LOX can act as substrates for key proteins required for effective autophagy and that cells deficient in this enzyme show evidence of autophagic dysfunction. The data functionally link phospholipid oxidation with autophagy for the first time. 12/15-Lipoxygenase-deficient macrophages show evidence of autophagic dysfunction. 12-HETE-PE is a substrate for LC2 and Atg8 lipidation. Macrophages deficient in 12/15-lipoxygenase show altered phospholipid content.
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