In all organisms, proteins need to be regulated throughout their life: when to be degraded and, possibly, substituted; where they need to be localised in the cell; and when they have to exert their function. A rapid way to ensure this regulation is by means of a modification called ubiquitination, a process through which proteins are flagged with a small protein called ubiquitin. This signature is read by other proteins that can interpret it either heading the tagged protein to programmed degradation or regulating its activity. Virtually all proteins in a cell can be modified through ubiquitination at defined moments of their life. Ubiquitination must therefore be tightly regulated and is controlled through a biochemical network that is necessary to attach ubiquitin to the specific target protein, either as a single entity or as a chain of several ubiquitins. The specificity of the ubiquitination process is guaranteed by E3 ubiquitin ligases, the enzymes that bring the substrate in close proximity to the ubiquitination machinery allowing the correct transfer of ubiquitin to the target protein. Ubiquitin tagging is a reversible process and deubiquitinating enzymes can erase this modification.
If the E3 ubiquitin ligases do not work properly, the consequences in the cells can be deleterious and indeed genetic and non-genetic alterations of these enzymes are associated with several pathological conditions.
The subject addressed by the TRIM-NET project was the study of a large family of E3 ubiquitin ligases, the Tripartite Motif (TRIM) proteins. Several TRIM proteins are implicated in common and rare human diseases and the goal of the project was the identification of disease mechanisms in which they are implicated to then be able to design therapeutic strategies. As TRIM proteins share a very similar domain structure, we established a scientific critical mass with complementary expertise bringing together a multidisciplinary international team that connects different competences on TRIM proteins: genetics, biochemistry, molecular and cell biology, chemical and structural biology.
The TRIM-NET research programme aimed at determining: i) how TRIM proteins contribute to disease and ii) how this information can help to develop therapeutic interventions. The parallel goal of the TRIM-NET consortium was to train young researchers in this area of biomedicine research preparing them for a future career in academia, industry or other science-related environments.
During the course of this project, we defined some of the pathological mechanisms involving TRIM E3 ubiquitin ligases in different diseases and some of these findings allowed the design and initial development of novel therapeutic strategies. These will be fully exploited to obtain possible drugs, thus heavily impacting on public health and eventually on society. The TRIM-NET outcomes will be also further developed scientifically as they are made available, through an open access mode, to the scientific community.
