Elucidating the H+ Coupled Zn2+ Transport Mechanism of ZIP4; Implications in Acrodermatitis Enteropathica

• Published in: International journal of molecular sciences Vol. 21; no. 3; p. 734
• Main Authors: Hoch, Eitan, Levy, Moshe, Hershfinkel, Michal, Sekler, Israel
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 22.01.2020; MDPI
• Subjects: Acidification; Antibodies; Efflux; Fluoroscopic imaging; Genetic diversity; Homeostasis; Immune system; Lymphocytes; Molecular modelling; Protein transport; Proteins; slc39a; zinc transport; zinc transporters, znt; zip structure function; zrt-irt-like proteins, zip
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21030734

Cellular Zn2+ homeostasis is tightly regulated and primarily mediated by designated Zn2+ transport proteins, namely zinc transporters (ZnTs; SLC30) that shuttle Zn2+ efflux, and ZRT-IRT-like proteins (ZIPs; SLC39) that mediate Zn2+ influx. While the functional determinants of ZnT-mediated Zn2+ efflux are elucidated, those of ZIP transporters are lesser understood. Previous work has suggested three distinct molecular mechanisms: (I) HCO3− or (II) H+ coupled Zn2+ transport, or (III) a pH regulated electrodiffusional mode of transport. Here, using live-cell fluorescent imaging of Zn2+ and H+, in cells expressing ZIP4, we set out to interrogate its function. Intracellular pH changes or the presence of HCO3− failed to induce Zn2+ influx. In contrast, extracellular acidification stimulated ZIP4 dependent Zn2+ uptake. Furthermore, Zn2+ uptake was coupled to enhanced H+ influx in cells expressing ZIP4, thus indicating that ZIP4 is not acting as a pH regulated channel but rather as an H+ powered Zn2+ co-transporter. We further illustrate how this functional mechanism is affected by genetic variants in SLC39A4 that in turn lead to Acrodermatitis enteropathica, a rare condition of Zn2+ deficiency.