Cespedes-Donoso Group | Post-Translational Control of Human Intercellular Communication

pablo.cespedes@ndm.ox.ac.uk

Our group focuses on how protein post-translational modification (PTM) enzymes modulate cell-cell communication in health and disease. PTMs diversify the biochemical and biophysical properties of proteins modulating trafficking, membrane diffusion, supramolecular organisation, stability, recycling, binding to cognate ligands and sorting into extracellular particles. Our mission is to discover the overarching hierarchy of enzymes modulating the intercellular networks of human immunity.

Although the human genome encodes more than 20,000 protein genes, human cells increase protein diversity by controlling the initiation and termination of RNA transcription and the splicing of messenger RNAs (mRNA), which are then used as blueprints for the synthesis of proteins in a process termed mRNA translation. Proteins, however, are far from being static entities and require further chemical modifications to participate in the dynamic processes supporting life. These modifications, commonly referred to as post-translational, lead to changes in protein trafficking, charge, topology, and affinity for other molecules such as lipids, sugars, and nucleic acids.

In the last decade, we have gained significant understanding of the crosstalk between bodily systems and the central role of the immune compartment in coordinating the function of the endocrine, nervous, cardiovascular, integumentary (skin), and digestive systems. Our immune cells also communicate with trillions of microbes inhabiting our integumentary and digestive systems, differentiating foes from friends.

Importantly, most host proteins participating in this multisystemic communication are post-translationally modified. However, our understanding of how PTMs regulate immune processes is rather limited. This is partly due to the fact that human evolution has selected a unique combination of enzymes catalyzing protein modifications, which are poorly replicated by experimental models, such as rodents and non-human primates.

As our group's long-term mission is to discover key human enzymes governing immune receptor functionality, we have developed a discovery framework harnessing our latest advancements in semi-synthetic biology. These technologies include synthetic antigen-presenting cells (sAPC) and lymphoid organoids supporting the dissection of T cell communication at different time and length scales, from hundred nanometers to millimeters, and from milliseconds to weeks. Our group will start investigating human-specific PTMs in the context of:

1. Citrullination of key peptidyl arginines required for cell-cell communication.

2. Sugars shaping receptor-ligand interactions unfolding at the T-cell glycocalyx.