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The loss of ATP2C1 impairs the DNA damage response and induces altered skin homeostasis: Consequences for epidermal biology in Hailey-Hailey disease.

ABSTRACT: Mutation of the Golgi Ca(2+)-ATPase ATP2C1 is associated with deregulated calcium homeostasis and altered skin function. ATP2C1 mutations have been identified as having a causative role in Hailey-Hailey disease, an autosomal-dominant skin disorder. Here, we identified ATP2C1 as a crucial regulator of epidermal homeostasis through the regulation of oxidative stress. Upon ATP2C1 inactivation, oxidative stress and Notch1 activation were increased in cultured human keratinocytes. Using RNA-seq experiments, we found that the DNA damage response (DDR) was consistently down-regulated in keratinocytes derived from the lesions of patients with Hailey-Hailey disease. Although oxidative stress activates the DDR, ATP2C1 inactivation down-regulates DDR gene expression. We showed that the DDR response was a major target of oxidative stress-induced Notch1 activation. Here, we show that this activation is functionally important because early Notch1 activation in keratinocytes induces keratinocyte differentiation and represses the DDR. These results indicate that an ATP2C1/NOTCH1 axis might be critical for keratinocyte function and cutaneous homeostasis, suggesting a plausible model for the pathological features of Hailey-Hailey disease.

SUBMITTER: Cialfi S

PROVIDER: S-EPMC4985699 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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The loss of ATP2C1 impairs the DNA damage response and induces altered skin homeostasis: Consequences for epidermal biology in Hailey-Hailey disease.

Cialfi Samantha S Le Pera Loredana L De Blasio Carlo C Mariano Germano G Palermo Rocco R Zonfrilli Azzurra A Uccelletti Daniela D Palleschi Claudio C Biolcati Gianfranco G Barbieri Luca L Screpanti Isabella I Talora Claudio C

Scientific reports 20160816

Mutation of the Golgi Ca(2+)-ATPase ATP2C1 is associated with deregulated calcium homeostasis and altered skin function. ATP2C1 mutations have been identified as having a causative role in Hailey-Hailey disease, an autosomal-dominant skin disorder. Here, we identified ATP2C1 as a crucial regulator of epidermal homeostasis through the regulation of oxidative stress. Upon ATP2C1 inactivation, oxidative stress and Notch1 activation were increased in cultured human keratinocytes. Using RNA-seq exper ...[more]

PMID: 27528123

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Project description:BackgroundHailey-Hailey disease (HHD) is an autosomal dominant cutaneous disorder that manifests as repeated blisters and erosions on flexural or intertriginous skin areas. The calcium-transporting ATPase type 2C member 1 gene (ATP2C1) encodes the secretory pathway Ca2+/Mn2+-ATPase 1 (SPCA1), whose deficiency is responsible for HHD. An ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was previously identified in a Han Chinese family with HHD.MethodsIn this study, the identified ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was investigated in transfected human embryonic kidney 293 cells to analyze its pathogenic mechanism in HHD patients by using cycloheximide chase assay, CCK8 assay and in silico modeling of SPCA1 mutant.ResultsCycloheximide chase assay showed that the degradation rate of the SPCA1 mutant was not obviously faster than that of the normal SPCA1. CCK8 assay showed that cell proliferation rates in the wild-type, A109_Q120del, and empty vector control groups all decreased in the gradient Mn2+ solutions in a dose-dependent manner. The cell proliferation rate in the wild-type was lower than that in the A109_Q120del and empty vector control (both P < 0.01), indicating overexpression of normal SPCA1 may rather induce Golgi stress, and even cell death. The cell proliferation rate in the A109_Q120del was lower than that in the empty vector control (P < 0.01), indicating that overexpression of the mutated SPCA1 may decrease its detoxification capability. Three-dimensional (3D) structure model of SPCA1 built by SWISS-MODEL and PyMOL showed that absence of the 12 amino acids from p.Ala109 to p.Gln120 in the SPCA1 mutant can cause obviously shortened transmembrane 2, which may affect correct localization of SPCA1 on the Golgi.ConclusionThese results demonstrate that the ATP2C1 mutation (c.325-2A>G, p.Ala109_Gln120del) may cause impaired SPCA1 capability to detoxify Mn2+ and abnormal SPCA1 structure, which reveals a new side for the pathogenesis of HHD.

Dataset Information

The loss of ATP2C1 impairs the DNA damage response and induces altered skin homeostasis: Consequences for epidermal biology in Hailey-Hailey disease.

Publications

The loss of ATP2C1 impairs the DNA damage response and induces altered skin homeostasis: Consequences for epidermal biology in Hailey-Hailey disease.

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