biostudies-literatureRathod MSwiss National Science FoundationOlga Mayenfisch StiftungSwiss Heart FoundationNovartis Foundation for Medical-Biological Researche202305006https://www.ebi.ac.uk/biostudies/studies/S-EPMC10937187biostudies-literatureUnknown223(4)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.The Journal of cell biologyDPM1 modulates desmosomal adhesion and epidermal differentiation through SERPINB5.PMC1093718719776422B086FF21098Beyersdorfer VLeal-Fischer KZimmermann ASchinner CHanns PSpindler VStudle CBuczak KWanuske MTRathod MFranz HfalseDPM1 modulates desmosomal adhesion and epidermal differentiation through SERPINB5.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.2024-01-01T00:00:00Z2024 Apr2025-04-04T20:24:49.803Z2025-04-04T20:24:49.803ZS-EPMC109371873847787810.1083/jcb.202305006