DPM1 modulates desmosomal adhesion and epidermal differentiation through SERPINB5

• Published in: The Journal of cell biology Vol. 223; no. 4; p. 1
• Main Authors: Rathod, Maitreyi, Franz, Henriette, Beyersdorfer, Vivien, Wanuske, Marie-Therès, Fischer, Karen Leal, Hanns, Pauline, Stüdle, Chiara, Zimmermann, Aude, Buczak, Katarzyna, Schinner, Camilla, Spindler, Volker
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 01.04.2024
• Subjects: Adhesion; Adhesive strength; Cell Adhesion; Cell Differentiation; Connecting; Cornea; Cytoskeleton; Defects; Desmoplakins; Development; Differentiation; Dolichol; Dolichols; Epidermis; Glycosylation; Humans; Keratinocytes; Localization; Phosphates; Phosphorylation; Proteomics; Serine; Skin; Thickness
• ISSN: 0021-9525; 1540-8140; 1540-8140
• DOI: 10.1083/jcb.202305006

Glycosylation is essential to facilitate cell-cell adhesion and differentiation. We determined the role of the dolichol phosphate mannosyltransferase (DPM) complex, a central regulator for glycosylation, for desmosomal adhesive function and epidermal differentiation. Deletion of the key molecule of the DPM complex, DPM1, in human keratinocytes resulted in weakened cell-cell adhesion, impaired localization of the desmosomal components desmoplakin and desmoglein-2, and led to cytoskeletal organization defects in human keratinocytes. In a 3D organotypic human epidermis model, loss of DPM1 caused impaired differentiation with abnormally increased cornification, reduced thickness of non-corneal layers, and formation of intercellular gaps in the epidermis. Using proteomic approaches, SERPINB5 was identified as a DPM1-dependent interaction partner of desmoplakin. Mechanistically, SERPINB5 reduced desmoplakin phosphorylation at serine 176, which was required for strong intercellular adhesion. These results uncover a novel role of the DPM complex in connecting desmosomal adhesion with epidermal differentiation.