FishTRIM aims to study the evolution and function of the TRIM family of proteins in fish. TRIM proteins are E3 ubiquitin ligases, which in essence means they "decide" which cellular proteins are going to be modified via ubiquitination - the addition of a small protein that leads to changes in protein stability, function or localization. The TRIM family has undergone massive expansions across the fish phylogeny, with single-copy mammalian TRIMs frequently present in large numbers in fish genomes. Additionally, these fish TRIMs seem to be rapidly evolving, with different fish groups showing different TRIM genes. In mammals, TRIM E3 ligases are key in host-pathogen interactions, regulating immune responses and also directly interacting with viral proteins in several cases. Similarly, various fish TRIMs have been associated to antiviral responses, and positive selection has been observed in fish TRIM protein domains involved in protein-protein interactions and pathogen recognition. However, fish TRIMs have been scarcely studied, and the drivers underpinning their expansion(s) in fish is not understood.
The hypothesis underlying FishTRIM is that this family of fish E3 ubiquitin ligases acts as an immune mechanism against specific viral pathogens, and therefore the repeated independent expansions of the TRIM repertoire in fish are the result of an arms race between fish and viruses. To address these questions, FishTRIM will study the function of this family in fish using a variety of approaches, including single-cell genomics to identify the cell types were they are active, genome editing to study their general function within the cells, or proteomics to identify the proteins they are targeting for ubiquitination. These results will be integrated with a phylogenomic approach, where the evolution of the TRIM repertoire across the fish phylogeny will be used to determine potential functional overlap across independent expansions, in addition to identifying selection patterns in the context of TRIM protein domains. Finally, using public databases and AI-powered protein structure prediction, the potential co-evolutionary interactions between fish TRIMs and viral proteins will be evaluated.
FishTRIM will illuminate the function of the expanded TRIM repertoire. The project aims to deliver frontier knowledge on the biological significance of the different fish TRIM expansions, with potential to revolutionise our understanding of fish immune systems and of ubiquitination in host-pathogen interactions. FishTRIM will also explore the role of TRIMs in resistance to viral diseases in fish, with potential transformative outcomes leading to improved fish welfare and food security.
