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- Title
O16 The novel roles of laminin α3 in epidermal barrier function and metabolism.
- Authors
Parzymies, Piotr; Jones, Eleri Mai; Mayes, Andrew; Messenger, David; O'Toole, Edel; Caley, Matthew
- Abstract
The skin serves an important barrier function performed by epidermal lipids, cornified epithelial cells and cell–cell adhesions. This function is compromised in old age and exhibits certain abnormalities such as flattened dermal–epidermal junction or improper lipid metabolism, and is also associated with mitochondrial dysfunction. The levels of a basement membrane protein laminin 332 have been shown to decrease as the skin ages. We have previously demonstrated that loss of laminin 332 leads to an upregulation of genes involved in cholesterol biosynthesis and is associated with an altered skin lipid profile. We showed that this change is caused by an abnormal intracellular cholesterol transport that is actin-dependent. To further elucidate the mechanism around cholesterol transport, we have identified five proteins of interest for further investigation. We have shown that two of those proteins, NPC2 and Myo5b, are decreased with the loss of the α3 laminin 332 subunit in laminin α3 knockdown nTERT keratinocytes vs. shC controls. Interestingly, the NPC2 binding partner, NPC1, appears to be increased in the laminin α3 knockdown nTERT keratinocytes. Our analysis has also demonstrated that e-cadherin, a crucial cell–cell adhesion protein, as well as several differentiation markers, are altered with the loss of laminin α3. We have carried out laminin 332 recovery experiments in two (2D) and three dimensions, which showed that the addition of recombinant laminin 332 restores the proper levels of myo5b and e-cadherin, suggesting a potential therapeutic effect. We have also performed proteomic, lipidomic, and transcriptomic studies in 2D, which demonstrated statistically significant changes (Q -value ≤ 0.01) in proteins involved in actin and microtubule regulation, cell–cell adhesion and showed unexpected mitochondrial metabolic changes associated with the loss of laminin α3. These findings show that laminin α3 plays numerous, previously unreported roles in epidermal lipid transport, cell–cell adhesion, differentiation and metabolism, and suggests a potential therapeutic role of the protein in skin ageing.
- Subjects
SKIN proteins; MEMBRANE proteins; LIPID metabolism; SKIN aging; BASAL lamina
- Publication
British Journal of Dermatology, 2023, Vol 189, Issue 1, pe11
- ISSN
0007-0963
- Publication type
Article
- DOI
10.1093/bjd/ljad174.016