Ubiquitin-dependent trafficking and turnover of the immune checkpoint protein CTLA4.

Most of the time our bodies' immune system operate with the brake on. This is crucial for self-tolerance and stops our cells being attacked indiscriminately. However, cancer cells can generate novel molecules which are recognised by our immune system.

Revving up the immune response in this context can be highly beneficial and this concept underpins what is now known as immunotherapy. Here, the immune system is let off the leash to fight the cancer, by removing the normal braking system.

The therapies that have been developed are antibodies which recognise cell surface receptors and block their interactions.

One of these receptors, called CTLA4, has a fleeting existence; after being made in the cell it will be gone within the hour. It is consigned to the cell's "rubbish dump" or "lysosome", to be recycled for parts.

Short-lived proteins, such as CTLA4, are normally recognised by other proteins which label them with a degradation tag or "signal" called ubiquitin. The identity of the protein that adds a ubiquitin tag onto CTLA4 and condemns it to be destroyed is unknown. We plan to discover it by sifting through about 600 candidates in a highly parallel fashion.

Alongside identifying this key molecule, we will also seek to understand any nuances of the CTLA4-ubiquitin signal and identify the molecules that recognise it and usher CTLA4 to the lysosome.

By understanding this basic cellular machinery that controls cellular CTLA4 levels we aim to open up new strategies for their adjustment in a therapeutically meaningful way.