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Mutations in sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) underlie Darier disease (DD), a dominantly inherited skin disorder characterized by loss of keratinocyte adhesion (acantholysis) and abnormal keratinization (dyskeratosis) resulting in characteristic mucocutaneous abnormalities. However, the molecular pathogenic mechanism by which these changes influence keratinocyte adhesion and viability remains unknown. We show here that SERCA2 protein is extremely sensitive to endoplasmic reticulum (ER) stress, which typically results in aggregation and insolubility of the protein. Depletion of ER calcium stores is not necessary for the aggregation but accelerates the progression. Systematic analysis of diverse mutants identical to those found in DD patients demonstrated that the ER stress initiator is the SERCA2 mutant protein itself. These SERCA2 proteins were found to be less soluble, to aggregate and to be more polyubiquitinylated. After transduction into primary human epidermal keratinocytes, mutant SERCA2 aggregates elicited ER stress, caused increased numbers of cells to round up and detach from the culture plate, and induced apoptosis. These mutant induced events were exaggerated by increased ER stress. Furthermore, knockdown SERCA2 in keratinocytes rendered the cells resistant to apoptosis induction. These features of SERCA2 and its mutants establish a mechanistic base to further elucidate the molecular pathogenesis underlying acantholysis and dyskeratosis in DD.