Promotion of vesicular zinc efflux by ZIP13 and its implications for spondylocheiro dysplastic Ehlers-Danlos syndrome

Significance Intracellular zinc is tightly controlled because zinc is essential but potentially toxic. Many organisms regulate zinc using storage vesicles/organelles, but whether mammals do so is unknown. Here, we show that human ZIP13 releases zinc from vesicular stores. Previous studies found that mutations in the ZIP13 gene, SLC39A13, cause the spondylocheiro dysplastic form of Ehlers-Danlos syndrome (SCD-EDS) and speculated that ZIP13 exports zinc from the early secretory pathway and that zinc overload in the endoplasmic reticulum causes SCD-EDS. In contrast, our study suggests that SCD-EDS results from zinc deficiency in the endoplasmic reticulum resulting from zinc trapping in vesicular stores

Measuring steady-state and dynamic endoplasmic reticulum and Golgi Zn2+ with genetically encoded sensors

Zn2+ plays essential roles in biology, and cells have adopted exquisite mechanisms for regulating steady-state Zn2+ levels. Although much is known about total Zn2+ in cells, very little is known about its subcellular distribution. Yet defining the location of Zn2+ and how it changes with signaling events is essential for elucidating how cells regulate this essential ion. Here we create fluorescent sensors genetically targeted to the endoplasmic reticulum (ER) and Golgi to monitor steady-state Zn2+ levels as well as flux of Zn2+ into and out of these organelles. These studies reveal that ER and Golgi contain a concentration of free Zn2+ that is 100 times lower than the cytosol. Both organelles take up Zn2+ when cytosolic levels are elevated, suggesting that the ER and Golgi can sequester elevated cytosolic Zn2+ and thus have the potential to play a role in influencing Zn2+ toxicity. ER Zn2+ homeostasis is perturbed by small molecule antagonists of Ca2+ homeostasis and ER Zn2+ is released upon elevation of cytosolic Ca2+ pointing to potential exchange of these two ions across the ER. This study provides direct evidence that Ca2+ signaling can influence Zn2+ homeostasis and vice versa, that Zn2+ dynamics may modulate Ca2+ signaling