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-␥ 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 hostpathogen interface.

Contribution of ATPase copper transporters in animal but not plant virulence of the crossover pathogen Aspergillus flavus

“…For example, Cu plays an important role in innate immune defense to microbial infection in mammals [8,11,12]. Previous studies demonstrated that, upon activation by a pathogen, macrophages elevate the expression levels of high-affinity Cu + importer Ctr1 and P-type Cu ATPase, ATP7A, leading to increased levels of Cu in the phagosome of IFN-γ stimulated macrophages [13,14]. These high Cu levels, together with Fe could react chemically with ROIs and reactive nitrogen intermediates (RNIs), potentially magnifying the Cu mediated toxicity.…”

Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis

“…Recent studies have extensively demonstrated the function of Cu as an antimicrobial agent. Levels of the mammalian Cu transporters (Ctr1 and ATP7A) in response to interferon-g or lipopolysaccharides are markedly induced in macrophage cell lines 4 . Alveolar immune cells from mice challenged with Cryptococcus express higher Ctr1 protein levels and accumulate intracellular Cu 5 .…”

Un rôle nouveau des métaux de transition dans l’immunité antimicrobienne

“…cuivre, ATP7A, s'accumule à la membrane des phagosomes dans des macrophages contenant des bactéries Escherichia coli, et que des mutants de E. coli déficients pour la pompe d'efflux CopA (permettant à la bactérie de résister à un excès de cuivre dans son environnement) sont détruits plus rapidement par les cellules immunitaires que la souche sauvage [5]. Les mycobactéries, dont les plus connues sont les agents de la lèpre et de la tuberculose, Mycobacterium leprae et Mycobacterium tuberculosis, possè-dent également des pompes d'efflux de métaux comme CopA (qu'on appelle des ATPases de type P).…”

“…Plusieurs décennies de recherche en neuropsychologie [1] et en neuro-imagerie [2] ont révélé que le traitement visuospatial est une fonction dominante de l'hémis-phère cérébral droit, construite grâce à l'interaction du lobe frontal avec le lobe pariétal [3]. Cependant, l'anatomie précise de cette dominance et l'organisation des connexions frontopariétales chez l'homme restaient jusqu'à ce jour inconnues [4,5].…”