A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity.
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.
White
Carine
C
Department of Nutritional Sciences, University of Missouri, Columbia, Missouri 65211, USA.
Lee
Jaekwon
J
Kambe
Taiho
T
Fritsche
Kevin
K
Petris
Michael J
MJ
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
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