title: Manganese redistribution by calcium-stimulated vesicle trafficking bypasses the need for P-type ATPase function.
abstract: Regulation of intracellular ion homeostasis is essential for eukaryotic cell physiology. An example is provided by loss of ATP2C1 function, which leads to skin ulceration, improper keratinocyte adhesion, and cancer formation in Hailey-Hailey patients. The yeast ATP2C1 orthologue PMR1 codes for a Mn(2+)/Ca(2+) transporter that is crucial for cis-Golgi manganese supply. Here, we present evidence that calcium overcomes the lack of Pmr1 through vesicle trafficking-stimulated manganese delivery and requires the endoplasmic reticulum Mn(2+) transporter Spf1 and the late endosome/trans-Golgi Nramp metal transporter Smf2. Smf2 co-localizes with the putative Mn(2+) transporter Atx2, and ATX2 overexpression counteracts the beneficial impact of calcium treatment. Our findings suggest that vesicle trafficking promotes organelle-specific ion interchange and cytoplasmic metal detoxification independent of calcineurin signaling or metal transporter re-localization. Our study identifies an alternative mode for cis-Golgi manganese supply in yeast and provides new perspectives for Hailey-Hailey disease treatment.
authors.affiliation: From the Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad de Sevilla, 41092, Sevilla, Spain and.
authors.forename: Néstor
authors.initials: N
authors.lastname: García-Rodríguez
authors.affiliation: the Departamento de Biolgía Celular-Instituto de Biomedicina de Sevilla (IBiS), Universidad de Sevilla, 41012 Sevilla, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Manzano-López
authors.affiliation: From the Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad de Sevilla, 41092, Sevilla, Spain and.
authors.forename: Miguel
authors.initials: M
authors.lastname: Muñoz-Bravo
authors.affiliation: From the Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad de Sevilla, 41092, Sevilla, Spain and.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Fernández-García
authors.affiliation: the Departamento de Biolgía Celular-Instituto de Biomedicina de Sevilla (IBiS), Universidad de Sevilla, 41012 Sevilla, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Muñiz
authors.affiliation: From the Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad de Sevilla, 41092, Sevilla, Spain and ralf.wellinger@cabimer.es.
authors.forename: Ralf Erik
authors.initials: RE
authors.lastname: Wellinger
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D020869:Gene Expression Profiling; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008345:Manganese / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D022161:Transport Vesicles / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; C102113:ATX2 protein, S cerevisiae; D027682:Cation Transport Proteins; D018832:Molecular Chaperones; C406793:SPF1 protein, S cerevisiae; C101767:SSC1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C416343:Smf2 protein, S cerevisiae; D049452:Green Fluorescent Proteins; D008345:Manganese; D000252:Calcium-Transporting ATPases; D002118:Calcium
keywords: Genetic Disease; Golgi; Manganese; PMR1; Vesicles; Yeast