As our understanding of zinc homeostasis in model organisms such as yeast becomes increasingly detailed, we still know very little about many basic aspects of zinc homeostasis in human cells. To address some of these questions, we have focused our studies on Zip13, the product of the SLC39A13 gene. Zip13 is a member of the ZIP family of metal ion transporters. Surprisingly, mutations in SLC39A13 were recently identified as causing a form of Ehlers-Danlos Syndrome (EDS), a connective tissue disease that results from defects in collagen modification and assembly. Given this intriguing link between Zip13 and EDS, it was of interest to us how a metal ion transporter contributes to this disease. In preliminary experiments, we have found that Zip13 is a zinc-specific transporter that localizes to a vesicular organelle in a wide variety of human cell types. The identity of these vesicles is not yet known. We propose the hypothesis that these vesicles are storage sites for zinc and that Zip13 is responsible for transporting this stored zinc out of those compartments under conditions of zinc deficiency. We further hypothesize that the defects in collagen assembly seen in EDS patients with SLC39A13 mutations result from ER zinc deficiency due to the trapping of zinc within its storage organelle. To test these hypotheses, we will a) assess the impact of Zip13 on cellular zinc homeostasis, b) determine the effect of Zip13 disruption on ER function, collagen hydroxylation, and ER zinc status, and c) determine whether Zip13 co-localizes to the zincosome, a vesicular site of zinc storage. Pursuit of these aims provides a unique opportunity to assess the function of vesicular zinc storage in mammalian zinc homeostasis. Zip13 may provide the first molecular handle with which to identify the organellar sites of zinc storage and characterize their function in mammalian cells.

Public Health Relevance

The processes of intracellular zinc transport and homeostasis are essential for basic cellular function, physiology, and human health. Despite this importance, however, we still know little about the specific transporter proteins involved and how they function in maintaining zinc homeostasis in human cells. This proposal is focused on Zip13, a zinc transporter recently linked to some cases of Ehlers-Danlos Syndrome, and the role this protein plays in controlling the vesicular storage of zinc.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM093303-03
Application #
8322785
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
Project Start
2010-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$227,873
Indirect Cost
$74,423
Name
University of Wisconsin Madison
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Jeong, Jeeyon; Eide, David J (2013) The SLC39 family of zinc transporters. Mol Aspects Med 34:612-9
Eide, David J (2011) The oxidative stress of zinc deficiency. Metallomics 3:1124-9