# The role of the ZNG1 metallochaperone in the host response to infection

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $539,750

## Abstract

SUMMARY
Zinc binding metalloproteins and metalloenzymes constitute approximately 10% of the vertebrate proteome and
are essential for many cellular processes. Due to the critical importance of zinc to vertebrate physiology, zinc
deficiency leads to growth defects, aberrant immune function, neurological disorders, cancers, and increased
risk of infection. This is a pervasive public health problem considering that approximately half of the world's
population suffers from dietary zinc deficiency, now the fifth most important risk factor for mortality in developing
countries. Although the clinical link between Zn deficiency and infection is established, the molecular
mechanisms are not well understood. Despite the known importance of zinc cofactors to cellular function, the
mechanism by which zinc is inserted into metalloproteins is poorly understood. In this application we report our
discovery of zinc-regulated GTPase metalloprotein activator 1 (Zng1) as the first reported zinc metallochaperone
that inserts zinc into cognate client metalloproteins. We identify the protein processing enzyme methionine
aminopeptidase 1 (Metap1) and the transcription factor zinc finger homeobox 3 (Zfhx3) as Zng1 clients, and we
describe a conserved domain that mediates an interaction between Zng1 and these metalloproteins. This finding
forms the basis of proposed structural, biochemical, and physiological experiments to define the mechanism of
Zng1-dependent metal delivery to client proteins. Single nucleotide polymorphisms in Zng1 are associated with
increased incidence of severe infections in humans, establishing an important link between Zng1 and infection
in the zinc starved host. Zng1-dependent metal transfer increases the functional activities of Metap1 and Zfhx3,
and loss of Zng1 activity in mice and zebrafish negatively impacts organismal development and increases
susceptibility to multiple infectious diseases. Based on these findings, we propose a model whereby the Zng1
family of enzymes are evolutionarily conserved metallochaperones that transfer zinc to Metap1 and Zfhx3 during
conditions of extreme zinc deficiency. We predict that this process of co-factor delivery leads to regulated protein
processing through Metap1 and coordinated gene expression changes through Zfhx3. Combined, these activities
help orchestrate the cellular response to infection during zinc starvation. Experiments described in this proposal
will test this model and determine the molecular mechanism by which Zng1 transfers metal to Metap1 and Zfhx3,
define the role of Zng1-client interactions in proteostasis and transcription, and reveal the in vivo contribution of
Zng1 metal delivery to vertebrate defense against infection. Collectively, findings from this proposal will uncover
the biological and pathophysiological relevance of this newly identified family of zinc metallochaperones and
make important contributions to nutrition and infection biology.

## Key facts

- **NIH application ID:** 10881931
- **Project number:** 5R01AI178929-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** DAVID P. GIEDROC
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $539,750
- **Award type:** 5
- **Project period:** 2023-07-05 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881931

## Citation

> US National Institutes of Health, RePORTER application 10881931, The role of the ZNG1 metallochaperone in the host response to infection (5R01AI178929-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10881931. Licensed CC0.

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