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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. Copyright © 2018 Kien et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.


Benedikt Kien, Susanne Grond, Guenter Haemmerle, Achim Lass, Thomas O Eichmann, Franz P W Radner. ABHD5 stimulates PNPLA1-mediated ω-O-acylceramide biosynthesis essential for a functional skin permeability barrier. Journal of lipid research. 2018 Dec;59(12):2360-2367

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PMID: 30361410

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