Background

Post-translational modifications (PTM) by members of the Ubiquitin (Ub) family represent an efficient way to regulate almost every biological process. Defects in this homeostatic equilibrium, result in pathologies such as cancer, neurodegeneration, inflammation or multiple infections. For this reason, this research area has become very attractive for fundamental scientists as well as for the pharmaceutical industry aiming to identify potential targets for therapeutic intervention.

The key scientific mission of the programme is to understand how protein modification with Ub/Ubls is generated (written), regulated (edited), recognised (read) and connected with effector functions (interpreted) to regulate cellular plasticity. Our main hypothesis is that the understanding of the “writers”, “editors”, “readers” and “interpreters” of this new universal language will help us to understand the encoded message. Importantly, this should allow us to charactersie physiologic and pathologic processes. Each of the model systems proposed in this programme will explore frontier questions that will provide insights on distinct aspects of this code.

Objectives

Objective 1.
Writing: Role of E3 ligases in chain formation (WP1)

Protein modification by members of the Ub family of modifiers is a highly dynamic reversible process regulated through the action of modifying and de-modifying enzymes. Each member of the Ub family has a set of enzymes with hierarchical organisation. Among those, we are particularly interested on the ligases (E3) that mediate protein modification. We aim to explore mechanisms of regulation of the activity and specificity for some of these enzymes and their role in determining chain composition.

Objective 2.
Editing: Role of De-modifying enzymes in generating Ub chain diversity (WP2)

Although the presence of heterologous chains is now undisputed, how, when and where those chains are formed is largely unknown and deserves multidisciplinary investigation. We aim to study the composition of distinct Ub chains, the order of deposition of the chain “building blocks” and factors involved. De-modifying enzymes (DUB), which are proteases specific for each protein modifier and their cofactors, play an important role in the editing process. The identification of enzymes and cofactors as key players in the construction of chains with distinct topology and architecture will be critical to determine potential targets for therapeutic intervention. This information will help us to establish the bases for a comprehensive understanding of the «Ubiquitin Code».

Objective 3:
Reading: Exploring the molecular mechanisms regulating chain recognition (WP3)

Ub chains contribute to protein remodelling and to the recognition of cellular targets by effector proteins. Although multiple domains of recognition of Ub and UbL molecules have been identified, little information is available about cellular factors contributing to regulate this recognition and the way these chains connect with distinct functions. Our aim is to better understand how these signals are recognised and identify the cis and trans elements playing a role in the specific recognition of distinct chains.

Objective 4.
Interpreting: Identification of biomarkers and drug targets (WP4).

Based on the present knowledge and on the knowledge obtained through our Research Programme, we will identify critical players in writing, editing or reading of the ubiquitin chains. We aim to validate critical enzymes and factors, previously or newly identified, as biomarkers for distinct diseases and use them to develop inhibitors of their function.