ABHD5 stimulates PNPLA1-mediated ω-O-acylceramide biosynthesis essential for a functional skin permeability barrier.
ABHD5 stimulates PNPLA1-mediated ω-O-acylceramide biosynthesis essential for a functional skin permeability barrier.
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DOI：
10.1194/jlr.m089771
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发表时间：
2018-12
影响因子：
6.5
通讯作者：
Radner FPW
中科院分区：
文献类型：
--
作者：
Kien B;Grond S;Haemmerle G;Lass A;Eichmann TO;Radner FPW
编码含马铃薯糖蛋白样磷脂酶结构域1（PNPLA 1）和含α/β-水解酶结构域5（ABHD 5）的基因突变（也称为比较基因鉴定58）是鱼鳞病（一种严重的皮肤屏障疾病）的病因。在这些基因中的任一个中具有突变的个体显示表皮ω-O-酰基神经酰胺（AcylCer）生物合成的缺陷，这表明PNPLA 1和ABHD 5在相同的代谢途径中起作用。在这份报告中，我们确定ABHD 5作为PNPLA 1的共活化剂，其刺激ω-羟基神经酰胺与亚油酸的酯化作用，用于AcylCer生物合成。ABHD 5与PNPLA 1相互作用，并将该酶募集到其推定的三酰甘油底物上，然后转移到胞质脂滴上。相反，携带与人类鱼鳞病相关的点突变的ABHD 5等位基因未能加速PNPLA 1介导的AcylCer生物合成。我们的研究结果建立了ABHD 5在与PNPLA 1相互作用以合成关键的表皮脂质方面的重要生化功能，强调了这些蛋白质在功能性皮肤渗透屏障形成中的重要性。
Mutations in the genes coding for patatin-like phospholipase domain-containing 1 (PNPLA1) and α/β-hydrolase domain-containing 5 (ABHD5), also known as comparative gene identification 58, are causative for ichthyosis, a severe skin barrier disorder. Individuals with mutations in either of these genes show a defect in epidermal ω-O-acylceramide (AcylCer) biosynthesis, suggesting that PNPLA1 and ABHD5 act in the same metabolic pathway. In this report, we identified ABHD5 as a coactivator of PNPLA1 that stimulates the esterification of ω-hydroxy ceramides with linoleic acid for AcylCer biosynthesis. ABHD5 interacts with PNPLA1 and recruits the enzyme to its putative triacylglycerol substrate onto cytosolic lipid droplets. Conversely, alleles of ABHD5 carrying point mutations associated with ichthyosis in humans failed to accelerate PNPLA1-mediated AcylCer biosynthesis. Our findings establish an important biochemical function of ABHD5 in interacting with PNPLA1 to synthesize crucial epidermal lipids, emphasizing the significance of these proteins in the formation of a functional skin permeability barrier.