# Project 2 - Membrane trafficking in EBV malignancies:  Implication of deubiquitinase UCH-L1

> **NIH NIH P01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $287,947

## Abstract

Project 2 
Project Summary Abstract 
The implication of extracellular membrane vesicles such as exosomes, and membrane protrusions such as 
tunneling nanotubes, in intercellular trafficking networks opens a new perspective in understanding tumor 
development and progression. The ubiquitin system is one of the central regulators of biogenesis and function 
of exosomes and nanotubes, and infection with tumor viruses including Epstein-Barr Virus (EBV) results in 
deregulation of cellular functions by manipulation of this system during cell transformation. Studies in recent 
years clearly demonstrate that the spectrum of potential functions of the small evolutionarily conserved family 
of Ubiquitin C-terminal Hydrolases (UCHs) is much wider than was suspected. Among them, UCH-l1 is of 
special interest: recent studies including ours demonstrate that this unique deubiquitinase is closely involved 
not only in cell transformation and in primary tumor formation, but is a main regulator of cancer progression as 
well. Based directly on our previous studies and substantial preliminary data, we hypothesize that UCH-L1 is a 
major regulator of ubiquitin-dependent processes of intra- and inter-cellular trafficking in EBV-positive cancers. 
In Aim I, we will analyze how distinct biochemical functions of UCH-L1 are required for exosome biogenesis 
and sorting, and how the EBV major oncogene, Latent Membrane Protein 1 (LMP1), is involved in these 
processes. In Aim II, based on our recent discovery that N-cadherin is highly expressed in EBV-driven B-cell 
lymphomas, and co-localizes with UCH-L1 in these cells, we will explore the role of N-cadherin-based 
complexes in intercellular trafficking of pro-metastatic factors produced by EBV-positive cancer cells. The 
results in this Aim will clarify how tunneling nanotubes and exosomes produced by EBV-transformed cells 
change the tumor microenvironment by transferring pro-invasive factors to tumor stromal tissues. In Aim III we 
will investigate whether inhibition of UCH-L1 activity with specific small-molecule inhibitors that have anti- 
tumorigenic effects in cell culture will also be active in vivo against EBV B-cell lymphogenesis in humanized 
mice. We will determine whether UCH-L1 DUB activity is required for EBV-induced immortalization of normal 
human B-cells, and whether inhibition of UCH-L1 affects expression and function of EBV genes in latently 
infected cells as well as during viral reactivation. EBV is tightly linked to several highly invasive malignancies of 
lymphoid and epithelial origin; treatment of patients with these malignancies poses unique challenges, and 
outcomes remain poor. Since recent study has demonstrated a profound anti-metastatic effect of such UCH-L1 
inhibitor in a mouse model of invasive carcinoma, specific inhibitors of UCH-L1 enzymatic activity may offer an 
adjunct to existing therapies.

## Key facts

- **NIH application ID:** 9986671
- **Project number:** 5P01CA019014-41
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** JOSEPH S PAGANO
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $287,947
- **Award type:** 5
- **Project period:** — → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986671

## Citation

> US National Institutes of Health, RePORTER application 9986671, Project 2 - Membrane trafficking in EBV malignancies:  Implication of deubiquitinase UCH-L1 (5P01CA019014-41). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9986671. Licensed CC0.

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