title: A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity.
abstract: Copper is an essential micronutrient that is necessary for healthy immune function. This requirement is underscored by an increased susceptibility to bacterial infection in copper-deficient animals; however, a molecular understanding of its importance in immune defense is unknown. In this study, we investigated the effect of proinflammatory agents on copper homeostasis in RAW264.7 macrophages. Interferon-gamma was found to increase expression of the high affinity copper importer, CTR1, and stimulate copper uptake. This was accompanied by copper-stimulated trafficking of the ATP7A copper exporter from the Golgi to vesicles that partially overlapped with phagosomal compartments. Silencing of ATP7A expression attenuated bacterial killing, suggesting a role for ATP7A-dependent copper transport in the bactericidal activity of macrophages. Significantly, a copper-sensitive mutant of Escherichia coli lacking the CopA copper-transporting ATPase was hypersensitive to killing by RAW264.7 macrophages, and this phenotype was dependent on ATP7A expression. Collectively, these data suggest that copper-transporting ATPases, CopA and ATP7A, in both bacteria and macrophage are unique determinants of bacteria survival and identify an unexpected role for copper at the host-pathogen interface.
authors.affiliation: Department of Nutritional Sciences, University of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Carine
authors.initials: C
authors.lastname: White
authors.forename: Jaekwon
authors.initials: J
authors.lastname: Lee
authors.forename: Taiho
authors.initials: T
authors.lastname: Kambe
authors.forename: Kevin
authors.initials: K
authors.lastname: Fritsche
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Petris
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry; D001692:Biological Transport; D027682:Cation Transport Proteins / Q000378:metabolism*; D002460:Cell Line; D002570:Ceruloplasmin / Q000378:metabolism; D003300:Copper / Q000737:chemistry*; D000073840:Copper-Transporting ATPases; D029968:Escherichia coli Proteins; D015971:Gene Expression Regulation, Enzymologic; D006056:Golgi Apparatus / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism; D021381:Protein Transport
chemical_list: D000890:Anti-Infective Agents; C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D029968:Escherichia coli Proteins; D003300:Copper; D002570:Ceruloplasmin; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases; C000612460:copA protein, E coli