# Dissecting new mechanisms of lysosome quality control in health and disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $369,431

## Abstract

PROJECT SUMMARY
 Lysosomes function as critical nodes for macromolecular recycling, metabolic rewiring, and pro-growth
signaling in cells. Accordingly, defects in lysosome function underlie degenerative diseases and aging while
hyperactivation of lysosomes are associated with cancer. Prior studies have shown that highly aggressive
Pancreatic ductal adenocarcinoma (PDA) cells upregulate lysosome biogenesis and activity to facilitate
degradation, clearance and recycling of incoming cargo material delivered by increased rates of autophagy and
macropinocytosis. Whether qualitative differences endow PDA lysosomes with unique structural and functional
properties to cope with a higher demand for substrate clearance remains unknown. To answer this question, we
have conducted the first comparative proteomics analysis of lysosomes isolated from PDA versus normal cells
and have identified members of the Ferlin family of membrane repair factors, Myoferlin and Dysferlin, as
selectively enriched on the membrane of PDA lysosomes. We propose that Ferlin proteins confer
increased protection against lysosomal membrane stress in PDA cells.
 Ferlin proteins are normally localized on the plasma membrane of cell types subjected to heightened
mechanical stress, such as skeletal muscle, where they facilitate repair of the lipid bilayer. Accordingly, mutations
in DYSF are associated with two forms of muscular dystrophy whereby impaired membrane resealing
compromises myoblast maturation, fusion and plasma membrane repair. Therefore, we hypothesize that PDA
cells hijack and repurpose Ferlin proteins at the lysosome membrane to protect the integrity of this organelle. In
support of this hypothesis, our preliminary findings show that PDA lysosomes are more resistant to acute
chemically induced membrane permeabilization relative to normal cells. Mechanistically, lysosome localization
of MYOF is necessary and sufficient for maintenance of lysosome quality control and its suppression leads to
profound defects in lysosome morphology, PDA cell proliferation and in vivo tumor growth. The goal of this
study is to investigate how MYOF functions to protect the lysosome membrane in mechanistic detail and to
determine the impact of blocking lysosome quality control on cellular metabolism, pro-growth signaling and
disease progression. In summary, our discovery and proposed studies will be the first to determine a novel
function for Ferlin proteins at the lysosome membrane and provide insight into how enhanced lysosome quality
control regulates cellular homeostasis and disease pathogenesis.

## Key facts

- **NIH application ID:** 10186267
- **Project number:** 1R01CA260249-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Rushika Miriam Perera
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $369,431
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186267

## Citation

> US National Institutes of Health, RePORTER application 10186267, Dissecting new mechanisms of lysosome quality control in health and disease (1R01CA260249-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10186267. Licensed CC0.

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