LiZIP3 is a cellular zinc transporter that mediates the tightly regulated import of zinc in Leishmania infantum parasites

• Published in: Molecular microbiology Vol. 96; no. 3; pp. 581 - 595
• Main Authors: Carvalho, Sandra, Barreira da Silva, Rosa, Shawki, Ali, Castro, Helena, Lamy, Márcia, Eide, David, Costa, Vítor, Mackenzie, Bryan, Tomás, Ana M.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2015
• Subjects: Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cellular biology; Gene Expression Profiling; Genetic Complementation Test; Homeostasis; Leishmania infantum - enzymology; Leishmania infantum - genetics; Leishmania infantum - metabolism; Oocytes - enzymology; Oocytes - metabolism; Parasites; Protein expression; Protozoan Proteins - metabolism; Saccharomyces cerevisiae - enzymology; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - growth & development; Saccharomyces cerevisiae - metabolism; Substrate Specificity; Xenopus laevis; Zinc; Zinc - metabolism
• ISSN: 0950-382X; 1365-2958
• DOI: 10.1111/mmi.12957

Summary Cellular zinc homeostasis ensures that the intracellular concentration of this element is kept within limits that enable its participation in critical physiological processes without exerting toxic effects. We report here the identification and characterization of the first mediator of zinc homeostasis in Leishmania infantum, LiZIP3, a member of the ZIP family of divalent metal‐ion transporters. The zinc transporter activity of LiZIP3 was first disclosed by its capacity to rescue the growth of Saccharomyces cerevisiae strains deficient in zinc acquisition. Subsequent expression of LiZIP3 in Xenopus laevis oocytes was shown to stimulate the uptake of a broad range of metal ions, among which Zn2+ was the preferred LiZIP3 substrate (K0.5 ≈ 0.1 μM). Evidence that LiZIP3 functions as a zinc importer in L. infantum came from the observations that the protein locates to the cell membrane and that its overexpression leads to augmented zinc internalization. Importantly, expression and cell‐surface location of LiZIP3 are lost when parasites face high zinc bioavailability. LiZIP3 decline in response to zinc is regulated at the mRNA level in a process involving (a) short‐lived protein(s). Collectively, our data reveal that LiZIP3 enables L. infantum to acquire zinc in a highly regulated manner, hence contributing to zinc homeostasis. LiZIP3 is a cell‐surface zinc transporter whose expression is tightly regulated by zinc bioavailability. We addressed the mechanism underlying LiZIP3 decay when the concentration of zinc in the parasite environment is high. These elevated zinc concentrations lead to increased LiZIP3 mRNA destabilization and a consequent down‐regulation of the transporter. The destabilization process requires the untranslated regions of the gene and is mediated by a short‐lived protein.