ATP2C1 knockdown induces abnormal expressions of cytoskeletal and tight junction proteins mimicking Hailey–Hailey disease

Abstract Hailey–Hailey disease (HHD) is a rare, autosomal, dominant, and hereditary skin disorder characterized by epidermal acantholysis. The HHD-associated gene ATPase calcium-transporting type 2C member 1 (ATP2C1) encodes the protein secretory pathway Ca2 + ATPase1 (SPCA1), playing a critical role in HHD pathogenesis. Therefore, we aimed to investigate the effect of ATP2C1 knockdown on keratinocyte cultures that mimicked HHD. The levels of cytoskeletal and tight junction proteins such as SPCA1, P-cofilin, F-actin, claudins, occludin, and zonula occludens 1 were analyzed in skin biopsies and cultured ATP2C1 knockdown keratinocytes. The results showed decreased levels of these proteins in HHD skin lesions. Moreover, their levels decreased in human keratinocytes transfected with ATP2C1 short hairpin RNA, accompanied by morphological acantholysis. Furthermore, the proliferation and apoptosis of the keratinocytes as well as intracellular calcium concentrations in these cells were not affected. The present findings indicated that SPCA1 inhibition led to abnormal levels of the cytoskeletal and tight junction proteins in the keratinocyte cultures. Therefore, keratinocyte cultures can mimic HHD and can serve as an in vitro model, thereby helping develop treatment strategies against HHD.