Desmosomal cell cohesion and epidermal differentiation are modulated by dolichol phosphate mannosyltransferase 1 (DPM1) through SERPINB5-dependent mechanisms

Glycosylation is an essential mediator of cell-cell adhesion and epidermal differentiation. We used CRISPR/Cas9-based gene editing to determine the role of dolichol phosphate mannosyltransferase 1 (DPM1), a key enzyme for N- and O-glycosylation. DPM1 loss resulted in weakening of cell-cell adhesion, impaired localization of the desmosome components desmoplakin and desmoglein 2, and cytoskeletal organization defects in human keratinocytes. In a 3D organotypic human epidermis model, loss of DPM1 resulted in impaired differentiation with abnormally increased cornification, reduced thickness of non-corneal layers, and the formation of intercellular gaps in the epidermis. Using proteomic approaches, SERPINB5 was identified as novel interaction partner of desmoplakin, ameliorating the effects of DPM1 loss on cell-cell adhesion and epidermal differentiation. Further analysis showed that the changes induced by DPM1 and SERPINB5 loss were at least in part dependent on elevated TGF-β signalling. Together, we identify DPM1 through SERPINB5 as a novel regulator of cell-cell adhesion and differentiation.