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European Research Training to Decipher The Ub Code : identification of potential biomarkers and drug targets

Periodic Reporting for period 1 - UbiCODE (European Research Training to Decipher The Ub Code : identification of potential biomarkers and drug targets)

Reporting period: 2018-01-01 to 2019-12-31

Post-translational modifications (PTM) by members of the Ubiquitin (Ub) family represent an efficient way to regulate protein function at several levels: to change their localisation, activity, their interaction with partner proteins or their stability at the right time and cellular compartment, according to the cell requirements. 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 (Pharma) aiming to identify potential targets for therapeutic intervention. Interestingly, Ub and Ub-Like (UbL) proteins can modify themselves, forming intricate and complex chains. This landscape was recently expanded with the discovery of the formation of heterologous chains among UbL molecules including SUMO or NEDD8 but also other PTMs such as phosphorylation, acetylation or ribosylation. This unsuspected complexity of what is now called «The Ubiquitin Code», an unexplored universal language that needs to be deciphered to understand protein homeostasis and its associated pathologies. To decrypt this complex code requires joint collaborative multidisciplinary efforts at all levels, including the use of distinct molecular systems and model organisms and the latest technological developments to explore chemical, biochemical, molecular, pharmacological and clinical aspects of protein modification by members of the Ub family. UbiCODE represents an unprecedented effort to understand «the Ubiquitin Code» in an integrated manner.

Our key scientific challenge is to investigate how chain diversity is generated (written), regulated (edited), recognised (read) and connected with effector functions (interpreted) to regulate cellular plasticity. Our main hypothesis is that a better knowledge of the “writers”, “editors”, “readers” and “interpreters” of this new universal language will help us to understand the encoded message, which will be crucial to predict physiologic and pathologic processes.
PhD students have studied firstly various E3 ligases to understand how substrates are recognised, modified with distinct chains architectures in order to connect with distinct functions. Methods and working conditions have been optimised to detect and analyse the activity of these ligases in various biological models and in vitro.

To study chain edition, the role of de-modifying enzymes acting on ubiquitin and Ub-like molecules was investigated by ESRs. Conditions for purification and analysis of the action of proteases acting on NEDD8, SUMO, Ubiquitin were implemented in vitro and in vivo using various cell lines and model organisms. The analysis of their role on chain edition has allowed to reach some of the first conclusions.

UbiCODE fellows have also developed tools and technology to study the specific recognition of distinct ubiquitin-chains containing or not, other UbLs (SUMO or NEDD8), analyse their interactors, subcellular localization and function of modified substrates. Methodologies have been successfully implemented and working conditions set for in vitro and in cellulo analysis using distinct cellular models.

New tools have been developed by ESRs to identify inhibitors of distinct ligases of biomedical interest. This work entails active collaboration between several members of this consortium with complementary expertise. Some progress has been done towards the identification of inhibitors of ligases, the development of new tools for chain identification, as well as towards the identification of exploitation possibilities of new drugs and inhibitors.
- Enhancing the career perspectives and employability of early stage researchers
UbiCODE PhD students have engaged in an individual reflection on their career goals and expectations from the programme. Daily interaction with experienced researchers from both the academia and the private sector allowed them to clarify their career paths. Fellows will have the opportunity to participate in theoretical workshops to gain transferrable skills (grants writing, communication tools, business development etc.).

- Contribution to structuring doctoral/early stage research training at the European level
Research teams within beneficiary institutions appreciate the quality of the network’s activities and are showing a greater interest in European programmes and funding opportunities. Daily encounters and scientific exchanges within laboratories allow to sensitise non-UbiCODE researchers to the upsides of collaborative research programmes. Interactions with local doctoral schools also contribute to structuring doctoral and early stage research training at the European level by initiating collaborations and sharing practices.

- Strengthening European innovation capacity
Trans-border collaborations are expected to maximise the results and innovation capacity of each participating laboratory, as well as to favour the access to knowledge in the field of ubiquitin research. The programme involves interaction with the private sector, especially with pharmaceutical firms, which will surely enhance translational outcomes. Some UbiCODE research teams are expecting to patent technology and are working on developing spin-off companies.