Ricerc@Sapienza

Hailey-Hailey's disease (HHD) is a skin disease linked to mutations in ATP2C1 gene encoding Ca2+/Mn2+ ATPase localized on the Golgi; deregulations of this protein function are responsible for defects in the control of cytoplasmic calcium concentrations leading to alterations of the desmosomal junctions and to the loss of adhesion between epidermal keratinocytes. The disorder is manifested as blistering skin lesions that do not heal and susceptible to microbial infections. The precise mechanism through which mutations induce skin lesions is unknown. We need to expand our understandings on the role of ATP2C1 in skin biology, in order to delineate how its loss may contribute to HHD. It was found that ATP2C1 defective keratinocytes are characterized by an altered Notch1 signaling. Endocytosis and endosomal trafficking have emerged as important cell biological steps in the Notch signaling pathway; intracellular trafficking of Notch may result in either down- or up-regulation of signaling depending on how the receptor is sorted within the cell. Notch1 signaling influences many aspects of the skin homeostasis including differentiation and wound repair. The understandings of the relevant pathways influenced by the deregulated Notch signaling would provide perspectives for future novel pharmacological targets. HHD skin lesions do not heal and show recurrent infections, indicating that HHD keratinocytes might not respond well to challenges such as wounding or infection. The success of wound healing process depends on growth factors, cytokines and chemokines involved in cellular processes. HHD lesions are characterized by deregulated cytokine expression and decreased repair properties and, moreover, HHD patients have an increased susceptibility to skin infections. It could be important investigate the influence of deregulated cytokines on ATP2C1-defective keratinocytes proliferation, differentiation and wound repair mechanisms.