Manganese Redistribution by Calcium-stimulated Vesicle Trafficking Bypasses the Need for P-type ATPase Function

• Published in: The Journal of biological chemistry Vol. 290; no. 15; pp. 9335 - 9347
• Main Authors: García-Rodríguez, Néstor, Manzano-López, Javier, Muñoz-Bravo, Miguel, Fernández-García, Elisabet, Muñiz, Manuel, Wellinger, Ralf Erik
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.04.2015; American Society for Biochemistry and Molecular Biology
• Subjects: ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Calcium - metabolism; Calcium - pharmacology; Calcium-Transporting ATPases - genetics; Calcium-Transporting ATPases - metabolism; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Endoplasmic Reticulum - metabolism; Endosomes - metabolism; Gene Expression Profiling; Genetic Disease; Golgi; Golgi Apparatus - metabolism; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Humans; Manganese; Manganese - metabolism; Metabolism; Microscopy, Fluorescence; Molecular Chaperones; Mutation; Oligonucleotide Array Sequence Analysis; PMR1; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Transport Vesicles - drug effects; Transport Vesicles - metabolism; Vesicles; Yeast; PMR1; Vesicles; Golgi; Yeast; Genetic Disease; Manganese
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M114.616334

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 Mn2+/Ca2+ 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 Mn2+ transporter Spf1 and the late endosome/trans-Golgi Nramp metal transporter Smf2. Smf2 co-localizes with the putative Mn2+ 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. Background: Yeast is a model system for the study of mechanisms governing eukaryotic Golgi-Mn2+ homeostasis. Results: We provide evidence that calcium stimulates ER and late endosome/trans- to cis-Golgi manganese delivery and bypasses the need for Pmr1. Conclusion: Vesicle trafficking promotes organelle-specific ion interchange and cytoplasmic metal detoxification. Significance: Our findings open new perspectives on chemical modifiers of Hailey-Hailey disease.