Actin Reorganization Is Abnormal and Cellular ATP Is Decreased in Hailey-Hailey Keratinocytes

Abstract

Actin reorganization and the formation of adherens junctions are necessary for normal cell-to-cell adhesion in keratinocytes. Hailey-Hailey disease (HHD) is blistering skin disease, resulting from mutations in the Ca2+ ATPase ATP2C1, which controls Ca2+ concentrations in the cytoplasm and Golgi of human keratinocytes. Because actin reorganization is among the first responses to raised cytoplasmic Ca2+, we examined Ca2+-induced actin reorganization in normal and HHD keratinocytes. Even though HHD keratinocytes display raised baseline cytoplasmic Ca2+, we found that actin reorganization in response to Ca2+ was impaired in HHD keratinocytes. Defects in actin reorganization were linked to a marked decrease in cellular ATP in HHD keratinocytes, which persists, in vivo, in HHD epidermis. Defective actin reorganization was reproduced in normal keratinocytes in which the intracellular ATP concentration had been lowered pharmacologically. ATP concentrations in undifferentiated keratinocytes markedly declined after extracellular Ca2+ was increased, but then recovered to a new baseline that was approximately 150% of the previous baseline. In contrast, ATP concentrations in HHD keratinocytes did not change in response to increased extracellular Ca2+. This report provides new insights into how the ATP2C1-controlled ATP metabolism mediates Ca2+-induced cell-to-cell adhesion in normal keratinocytes. In addition, these findings implicate inadequate ATP stores as an additional cause in the pathogenesis of HHD and suggest novel therapeutic options.

Unique characteristics of Ca 2+ homeostasis of the trans -Golgi compartment

“…The present data provide additional information on the functional role of TG Ca 2+ . In particular, recent evidence suggests that SPCA1 down-regulation (in cell culture or in knockout animals) affects a number of cellular and GA-specific functions, from GA morphology to apoptosis and from neuronal differentiation to protein trafficking (13,(36)(37)(38)(39). Here we have further expanded this analysis by acutely down-regulating SPCA1 expression using the RNAi technique.…”

Direct Comparison of Manganese Detoxification/Efflux Proteins and Molecular Characterization of ZnT10 Protein as a Manganese Transporter

“…In contrast to these proteins, SPCA1 and ZnT10 operate to detoxify/efflux manganese via exporting manganese to an extracellular site in vertebrate cells. Our results indicate that ZnT10 is a primary contributor in the detoxification/efflux of manganese, which may reflect that only mutations to the ZnT10 gene have been identified as parkinsonism, although mutations of the SPCA1 gene results in Hailey-Hailey diseases (MIM accession number 169600), which is thought to be related to calcium levels and not to disturbances in manganese metabolism (57).…”

Novel Mechanisms of Target Cell Death and Survival and of Therapeutic Action of IVIg in Pemphigus

“…In this regard, it is worth noting that cellular ATP is decreased in keratinocytes in familial benign pemphigus (a.k.a. Hailey-Hailey disease) 57 that display cytopathological features characteristic of acantholytic cells of PV. 5 The morphology of acantholytic cells in PV does not match that of either typical apoptotic or oncotic cells.…”