# Molecular mechanisms that regulate vesicle formation and transport

> **NIH NIH R35** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $497,564

## Abstract

PROJECT SUMMARY
How the intracellular membrane system of eukaryotic cells is configured and maintained is a fundamental
problem in cell biology. Deficiencies in this organization often lead to disease. The overarching goal of my
laboratory is to define the molecular mechanisms that regulate membrane dynamics, including vesicle
biogenesis, organelle trafficking, and protein sorting in the early secretory and endocytic pathways of metazoan
cells. We aim to determine how normal membrane transport contributes to cellular homeostasis and understand
the molecular basis for disease states that emerge when trafficking pathways are disrupted. Using a combination
of model systems, structural biology, biochemistry, genetics, and high-resolution subcellular imaging, our studies
focus on two essential trafficking pathways necessary for protein and lipid export from the endoplasmic reticulum
(ER) and protein turnover within lysosomes via a multivesicular endosome (MVE) intermediate. Mutations in
several factors that regulate these processes have been implicated in cancer, diabetes, immune dysfunction,
and neurodegeneration. Thus, deciphering the fundamental principles underlying the regulation of ER export
and MVE biogenesis should facilitate the future identification of therapeutic targets for disease intervention. One
major focus of my research has been elucidating how the early secretory pathway is organized. Our findings
revealed the existence of a conserved membrane interface, which links subdomains on the endoplasmic
reticulum (ER) that produce COPII-coated transport carriers to juxtaposed ER-Golgi intermediate compartments
(ERGIC). We identified Trk-fused gene (TFG) as a key constituent of this interface and have shown that its
inhibition uncouples ER and ERGIC membranes and leads to the isotropic diffusion of COPII-coated carriers,
reducing the efficiency of cargo secretion. My second research focus is aimed at understanding the mechanisms
that direct the formation of MVEs, which bud intralumenal vesicles (ILVs) into their interior to sequester
membrane-associated cargoes from the cytoplasm. Eventual fusion of MVEs with lysosomes results in the
degradation of ILVs and their associated proteins, which plays a key role in tumor suppression by governing the
capture and sequestration of signaling receptors. Using C. elegans, we have developed a new, highly simplified,
and genetically tractable system to investigate how components of the endosomal sorting complex required for
transport (ESCRT) machinery enables the movement of endocytosed cargo to MVEs and ILVs in the context of
an intact, developing animal. Our future work will continue to capitalize on evolving methodologies to further
establish how COPII-mediated transport and ESCRT-mediated MVE biogenesis are properly regulated. A better
understanding of these processes will yield key insights into the homeostatic controls that sustain normal protein
trafficking in the secretory and endocytic pathways d...

## Key facts

- **NIH application ID:** 9850778
- **Project number:** 1R35GM134865-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Anjon Audhya
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $497,564
- **Award type:** 1
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850778

## Citation

> US National Institutes of Health, RePORTER application 9850778, Molecular mechanisms that regulate vesicle formation and transport (1R35GM134865-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9850778. Licensed CC0.

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