# Regulation of Cellular Zinc Homeostasis

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $328,952

## Abstract

PROJECT SUMMARY
Zinc is an essential nutrient because it is a required cofactor for many proteins. Therefore, cells have evolved
with efficient mechanisms to maintain zinc homeostasis during zinc deficiency. Cells can also alter specific
metabolic processes to adapt to zinc deficiency. Among eukaryotes, these mechanisms are best understood in
the yeast Saccharomyces cerevisiae. In this yeast, the Zap1 transcription factor is the central regulator of zinc
homeostasis. Over the years, analysis of Zap1 and its target genes has led to many key discoveries about how
cells survive and thrive during zinc deficiency. In this application, three specific aims are proposed that build on
that solid foundation of prior work. Translation of the mRNAs for zinc-binding proteins generates apoproteins
that rapidly bind their metal cofactor to become stably folded. During zinc deficiency, we propose that zinc
proteins are synthesized but are largely unable to bind the metal because of its limited supply. The resulting
accumulation of unmetalated apoproteins greatly disrupts protein homeostasis. We have discovered many
mechanisms cells use to diminish and adapt to this stress. In Aim 1, we will further test the hypothesis of
abundant apoproteins by identifying specific zinc proteins that are not metalated during zinc deficiency. These
studies will provide unprecedented insights into the trafficking of zinc within cells. We will then determine the
role of the Tsa1 protein chaperone in stabilizing those apoproteins so that they can be efficiently metalated
when zinc levels increase. Tsa1 is critical for growth during zinc deficiency and these studies will define the
molecular basis of this protein’s important function. In Aim 2, we will investigate the role of the proteasome-
ubiquitin system in degrading apoproteins and the role of protein quality control compartments (IPOD, JUNQ)
in sequestering misfolded apoproteins and mediating their degradation by autophagy. These studies will
establish an integrated model of protein homeostasis during zinc deficiency. Finally, in Aim 3, we will test how
the model of protein homeostasis during zinc deficiency that we have generated for yeast applies to human
cells. We will assess whether the large abundance of apoproteins during zinc deficiency is an evolutionarily
conserved stress and we will test the role of human Tsa1 orthologs in tolerating that stress and facilitating the
binding of zinc when its supplies increase. This research has clear relevance for human health because zinc
deficiency is a common nutrient deficiency in the US population. Our analysis of the effect of zinc deficiency on
protein homeostasis may ultimately lead to fundamental insights into diseases of protein misfolding such as
amyotrophic lateral sclerosis (ALS), Parkinson’s, Alzheimer’s, and prion diseases and their relationships with
metal homeostasis. In addition, zinc homeostasis in fungi and other microbes is critical for pathogenesis. We
are illumin...

## Key facts

- **NIH application ID:** 10425374
- **Project number:** 5R01GM056285-23
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** David J Eide
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $328,952
- **Award type:** 5
- **Project period:** 1997-09-30 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425374

## Citation

> US National Institutes of Health, RePORTER application 10425374, Regulation of Cellular Zinc Homeostasis (5R01GM056285-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10425374. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*