title: Glutathione S-transferase ϴ-subunit as a phenotypic suppressor of pmr1Δ strain, the Kluyveromyces lactis model for Hailey-Hailey disease.
abstract: Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is a rare, chronic and recurrent blistering disorder, histologically characterized by suprabasal acantholysis. HHD has been linked to mutations in ATP2C1, the gene encoding the human adenosine triphosphate (ATP)-powered calcium channel pump.
  
  
  
  In this work, the genetically tractable yeast Kluyveromyces lactis has been used to study the molecular basis of Hailey-Hailey disease. The K. lactis strain depleted of PMR1, the orthologue of the human ATP2C1 gene, was used to screen a Madin-Darby canine kidney (MDCK) cDNA library to identify genetic interactors able to suppress the oxidative stress occurring in those cells.
  
  
  
  We have identified the Glutathione S-transferase ϴ-subunit (GST), an important detoxifying enzyme, which restores many of the defects associated with the pmr1Δmutant. GST overexpression in those cells suppressed the sensitivity to calcium chelating agents and partially re-established calcium (Ca2+) homeostasis by decreasing the high cytosolic Ca2+levels in pmr1Δstrain. Moreover, we found that in the K. lactis mutant the mitochondrial dysfunction was suppressed by GST overexpression independently from calcineurin. In agreement with yeast results, a decreased expression of the human GST counterpart (GSTT1/M1) was observed in lesion-derived keratinocytes from HHD patients.
  
  
  
  These data highlighted the Glutathione S-transferase as a candidate gene associated with Hailey-Hailey disease.
  
  
  
  Kluyveromyces lactis can be considered a good model to study the molecular basis of this pathology.
authors: Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy.
authors: G
authors: G
authors: Ficociello
authors: Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy.
authors: E
authors: E
authors: Zanni
authors: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors: S
authors: S
authors: Cialfi
authors: Porphyria Center, San Gallicano Institute IRCCS, Rome, Italy.
authors: C
authors: C
authors: Aurizi
authors: Porphyria Center, San Gallicano Institute IRCCS, Rome, Italy.
authors: G
authors: G
authors: Biolcati
authors: Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy.
authors: C
authors: C
authors: Palleschi
authors: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy,. Electronic address: claudio.talora@uniroma1.it.
authors: C
authors: C
authors: Talora
authors: Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy. Electronic address: daniela.uccelletti@uniroma1.it.
authors: D
authors: D
authors: Uccelletti
mesh_terms: D000818:Animals; D000252:Calcium-Transporting ATPases / Q000172:deficiency / Q000235:genetics; D004285:Dogs; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015966:Gene Expression Regulation, Fungal; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015603:Keratinocytes / Q000201:enzymology* / Q000473:pathology; D007716:Kluyveromyces / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D061985:Madin Darby Canine Kidney Cells; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D016506:Pemphigus, Benign Familial / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010641:Phenotype
chemical_list: D005656:Fungal Proteins; D006861:Hydrogen Peroxide; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase; D000252:Calcium-Transporting ATPases
keywords: ATP2C1; Calcium; Glutathione S-transferase; Keratinocytes; Oxidative stress; PMR1