# Membrane trafficking to lysosomes

> **NIH NIH R35** · UNIVERSITY OF COLORADO · 2024 · $71,832

## Abstract

PROJECT SUMMARY
Lysosomes are the primary catabolic site of cells, serving to degrade extracellular material internalized by endocytosis
and intracellular components earmarked for turnover. These items and the hydrolytic enzymes that
degrade them are delivered to lysosomes by multiple membrane trafficking pathways, which are operated by
cellular protein machineries that are evolutionarily conserved from yeast to man. Mutations that disrupt the activities
of these machineries are linked to genetic diseases, and pathogens exploit these trafficking pathways to
establish infection. Many of the molecular mechanisms that operate membrane trafficking machineries are unknown.
My lab addresses fundamental questions about membrane trafficking to lysosomes using the budding
yeast Saccharomyces cerevisiae as a genetically tractable model organism. The major questions we plan to
address over the next five years include the following. 1) What are the physiological mechanisms that regulate
the trafficking of cell-surface receptors to the hydrolytic interior of the lysosome? This trafficking pathway functions
at endosomes to sort endocytosed receptors into membrane-enclosed transport vesicles that are delivered
into the lysosome lumen. Recent progress from my lab has revealed that the formation of these vesicles
is coordinated with other processes that are vital to cellular physiology, including ubiquitin protein homeostasis
and endocytic pH regulation. We plan to identify the machineries that interface these different cellular systems
and determine how they exert control over the protein machinery that mediates the formation of vesicles transported
to the lysosome lumen. These results will define ways in which receptor degradation is coordinated with
cellular physiology. 2) What are the mechanisms that mediate the delivery of newly synthesized transmembrane
proteins that are destined to function at the lysosomal membrane? Using novel genetic tools we created
for discovery and diagnostics, we recently identified two specific cellular machineries and several additional
candidate machineries that function in this trafficking pathway. We plan to define the mechanisms by which
these machineries function in transport, which will establish fundamental principles that underly the biogenesis
of lysosomes. Our work is bolstered by ongoing productive collaborations that employ diverse interdisciplinary
techniques, including high-resolution microscopy, biophysical analyses of protein assemblies reconstituted in
vitro, proteomics, and genetic screening. Moving forward, our overall vision is to continue exploiting yeast for
discovering and mechanistically understanding membrane trafficking to lysosomes while also addressing the
extent to which these mechanisms are conserved in human cells. The information gained from this work will
provide an understanding of how membrane trafficking pathways to lysosomes operate under normal physiological
conditions and how they are vulnera...

## Key facts

- **NIH application ID:** 11030651
- **Project number:** 3R35GM149202-02S1
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** CHARLES G ODORIZZI
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $71,832
- **Award type:** 3
- **Project period:** 2023-05-04 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11030651

## Citation

> US National Institutes of Health, RePORTER application 11030651, Membrane trafficking to lysosomes (3R35GM149202-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11030651. Licensed CC0.

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