# Dissecting intracellular metabolite trafficking using chemoproteomics

> **NIH NIH R35** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $388,750

## Abstract

ABSTRACT
Signaling metabolites control various cellular processes, including cell cycle, differentiation, and adaptations to
environmental stimuli. Intracellular trafficking of signaling metabolites is crucial for maintaining cellular
homeostasis and integrate metabolic and transcriptional responses. Defects in metabolite transport and
distribution may lead to multiple diseases, including cancer, immunological, inflammatory, and metabolic
disorders. Subcellular compartmentalization allows the same molecules to partake in distinct biological
processes. Signaling metabolites generally act as second messengers for specific proteins or ligands for sensors
and nuclear receptors (NR), ligand-activated transcription factors that sense environmental signals and drive
cellular response. Because of their intrinsic reactivity, the intracellular levels of NR ligands, along with their
subcellular localization, are tightly controlled and may oscillate greatly depending on nutritional states and
pathophysiological conditions. Despite our understanding of their functions, our knowledge of how nuclear
receptor ligands travel across organelles remains limited due to the lack of specific tools to target such
mechanisms. We propose to integrate chemoproteomics, metabolomics, and cellular assays, to develop novel
chemical tools to interrogate the protein interactomes of NR ligands and identify their intracellular chaperones.
Leveraging these technologies, we intend to reveal the molecular and functional basis of intracellular trafficking
of signaling metabolites and identify dedicated protein chaperones that bind NR ligands at their site of synthesis
or entry into the cell, transport them to the nucleus, and deliver them to NRs. A driving finding of our preliminary
work was the discovery of PGRMC2 as an intracellular heme chaperone that transports heme from mitochondria
to the nucleus and regulates the transcriptional activity of heme-responsive transcription factors such as Rev-
Erb and BACH1. We will use the experience acquired from this initial work to extend our studies to the
identification of other transport mechanisms for known NR ligands, such as fatty acids, that activate PPARs, a
family of ligand-activated transcription factors that regulate metabolism and systemic energy homeostasis. The
second major goal of this proposal is to develop spatial- and time-resolved protein-metabolite maps, which we
expect to go beyond the identification of intracellular trafficking mechanisms and have a broader impact on the
field by providing a powerful strategy to study metabolite-protein crosstalk. Lastly, this project uniquely combines
our multidisciplinary expertise in transcriptional regulation, metabolism, and chemical biology to lead the
exploration of a new exciting findings in cell biology.

## Key facts

- **NIH application ID:** 10896408
- **Project number:** 5R35GM150899-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Andrea Galmozzi
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896408

## Citation

> US National Institutes of Health, RePORTER application 10896408, Dissecting intracellular metabolite trafficking using chemoproteomics (5R35GM150899-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10896408. Licensed CC0.

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