Abstract
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.
Highlights
Mutations in the genes coding for patatin-like phospholipase domain-containing 1 (PNPLA1) and / hydrolase domain-containing 5 (ABHD5), known as comparative gene identification 58, are causative for ichthyosis, a severe skin barrier disorder
Our data demonstrate that / -hydrolase domain-containing 5 (ABHD5) interacts with PNPLA1 and targets the enzyme onto lipid droplets
This process is assumed to facilitate the access of PNPLA1 to its putative TAG acyl-donor substrate, thereby stimulating the a defect in epidermal -Oacylceramide (AcylCer) biosynthesis required for a functional skin permeability barrier
Summary
Mutations in the genes coding for patatin-like phospholipase domain-containing 1 (PNPLA1) and / hydrolase domain-containing 5 (ABHD5), known as comparative gene identification 58, are causative for ichthyosis, a severe skin barrier disorder. Mutations in genes that are involved in either the synthesis, secretion, or processing of barrier lipids lead to a defective skin permeability barrier and concomitantly to the pathophysiology of ichthyosis [10, 11]. This rare scaling disorder is characterized by epidermal hyperplasia that results in the formation of multiple layers of corneocytes (hyperkeratosis) and abnormal desquamation leading to the detachment of large SC flakes [10,11,12,13,14]. Since the first ichthyosis consensus conference [11], the various forms of the disease are classified into nonsyndromic ichthyoses, in which the disease is limited to the skin, and syndromic ichthyoses, where the disorder affects other tissues and organs
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