ABHD5 and PNPLA1 Function in the Skin

The skin is the bodys largest organ whose key function is to provide a barrier to the loss of water and electrolytes. This permeability barrier function is located in the outermost layer of the skin, the stratum corneum, and largely depends on the presence of lipids, especially -O-acylceramides (AcylCer). Mutations in genes involved in the biosynthesis of AcylCer lead to a skin barrier disorder, termed ichthyosis. We identified such disease-causing mutations in the PNPLA1 (patatin-like phospholipase domain-containing 1) and the ABHD5 (a/ß-hydrolase domain-containing 5) gene in humans and mice that lead to a very similar ichthyosis pathology. The skin of affected individuals lacks AcylCer but accumulates the precursor lipids for AcylCer formation. Based on our preliminary findings, we hypothesize that ABHD5 interacts with PNPLA1. This protein interaction stimulates the enzymatic activity of PNPLA1 essential to catalyze the final step in AcylCer biosynthesis. In the proposed project, we therefore aim to characterize the protein-protein interaction between PNPLA1 and ABHD5 and analyze whether PNPLA1 requires the presence of ABHD5 to efficiently synthesize AcylCer in the skin of humans and mice. Finally, we will investigate the biosynthesis and degradation of a newly identified lipid species in the skin as well as its role in AcylCer synthesis. The results of our study will reveal the molecular mechanisms leading to ichthyosis development in humans with PNPLA1 or ABHD5 mutations. In summary, our findings will significantly contribute to the understanding of the epidermal lipid metabolism and its role in the development and progression of skin diseases, such as ichthyosis and atopic dermatitis, but also of disorders like allergic asthma or allergies.