# Deciphering Novel Principles of Rapid Proteostatic Control and Innovating Spatiotemporal Lysosomal Tools

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $380,540

## Abstract

PROJECT ABSTRACT
Proteome integrity is maintained by a complex network that regulates protein synthesis, folding,
transport, and degradation. Lysosomes are the catabolic center of a cell and central to
maintaining proteome homeostasis by preventing, detecting, and removing abnormal proteins.
Major knowledge gaps remain in the regulation, structural components, and substrate
specificities of lysosomal substrates. Intracellular proteolysis through the ubiquitin-proteasome
system has been the most well-characterized eukaryotic proteolytic pathway as the protein
targeting by ubiquitin and the amino acid sequences recognized by E3 ubiquitin ligases are
well-defined. In contrast, a major obstacle in understanding lysosomal processes is the
incomplete knowledge of protein modifications that enable lysosomal trafficking mechanisms.
Our work identified that arginine methylation leads to protein delivery into lysosomes for
degradation. We showed that rapid methyl-driven delivery was essential for removing enzymes
from the cytosol to promote growth and proliferation. The proposed studies examine the central
hypothesis that methyl-driven lysosomal proteolysis is a widespread process that enables
natural protein turnover during homeostasis and rapid protein remodeling in response to
external stimuli. We address this hypothesis in three areas of research. Area 1 defines novel
protein substrates and the peptide motifs required for lysosomal delivery. Area 2 determines the
functional impact of rapid methyl-driven delivery as a control mechanism for fundamental
cellular metabolic pathways. Area 3 leverages naturally-occurring lysosomal protein signals to
develop tools for researchers to rapidly decrease protein levels in endogenous living systems.
We test the conceptually novel model that selective lysosomal proteolysis is central for
regulating cytosolic, short-lived proteins that were previously thought to be degraded in
proteasomes. We anticipate use of our publicly available database of novel methyl-degraded
lysosomal proteins will provide an essential resource for the fields studying protein control. We
develop technically innovative tools to gain new mechanistic insight into lysosomal biology for
the present studies while also providing a tool for the broader research community that
significantly improves current strategies for endogenous protein depletion.
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## Key facts

- **NIH application ID:** 11022697
- **Project number:** 1R35GM157370-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Lauren Veronica Albrecht
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $380,540
- **Award type:** 1
- **Project period:** 2024-09-20 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11022697

## Citation

> US National Institutes of Health, RePORTER application 11022697, Deciphering Novel Principles of Rapid Proteostatic Control and Innovating Spatiotemporal Lysosomal Tools (1R35GM157370-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11022697. Licensed CC0.

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