Dr Virginia De Cesare

Investigating the hidden code of ubiquitin and how it controls human health and disease

Cells use a tiny protein called ubiquitin as a molecular tag to control what happens to other proteins. Disruption of ubiquitin pathways is linked to a wide range of human diseases, including neurodegeneration and cancer, and understanding these mechanisms opens new opportunities for therapeutic targeting.

For many years scientists believed that ubiquitin was attached only to one specific building block of proteins called lysine (canonical ubiquitylation, see fig. 1). We now know that ubiquitin can also be attached in unexpected ways to other amino acid, such as serine and threonine, but also sugars and nucleic acids (non-canonical ubiquitylation, see figure 1) revealing a hidden layer of cellular regulation that our research aims to uncover.

Non-canonical ubiquitylation represents a largely unexplored regulatory system with the potential to reshape our understanding of cell biology. By defining how non-canonical ubiquitylation works, De Cesare lab aims to build a more complete picture of ubiquitin biology and to establish new technological frameworks that can be applied across biology and biomedical research.

Using an interdisciplinary approach that combines quantitative proteomics, genomics, molecular biology, protein biochemistry and cell-based functional assays, our work investigates how ubiquitin is attached to alternative amino acids and biomolecules, and how these modifications influence protein behaviour and human health and disease.

Selected Publications 

1. Abdul Rehman, S.A., et al., Discovery and characterization of noncanonical E2-conjugating enzymes. Sci Adv, 2024. 10(13): p. eadh0123. 

2. De Cesare, V., et al., Deubiquitinating enzyme amino acid profiling reveals a class of ubiquitin esterases. Proc Natl Acad Sci U S A, 2021. 118(4). 

3. De Cesare, V., et al., High-throughput matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry-based deubiquitylating enzyme assay for drug discovery. Nat Protoc, 2020. 15(12): p. 4034-4057.

People in my lab

• Chiara Cazzaniga (Post-Doctoral Research Associate)
• Gabrielle Taylor (Research Technician)
• Hope Obasi (PhD Student)
• Valerio Perticaroli (Visiting PhD Student)

Other Research Activity

The De Cesare lab is actively developing MALDI-TOF/MS and LC–MS–based technologies with a strong focus on translation and commercialisation. This includes the expansion of established platforms such as the deubiquitylating enzyme (DUB) profiling service and KIPIK, enabling high-throughput, quantitative analysis of enzyme activity for both academic and industry partners. These efforts aim to bridge fundamental discovery with applied research by delivering robust, scalable mass spectrometry–based solutions for target validation, inhibitor screening, and mechanism-of-action studies.

• BS32037 Cell Signalling – contributor (Lecture Mass Spectrometry in Cell Signalling)
• Honours Year – project supervisor
• Integrated MSci – project supervisor