Ubiquitin biology is a key area of research in the LMB’s PNAC division, where David Komander’s group is working to unravel the emerging complexity in the ubiquitin system.

What is protein ubiquitination?

Ubiquitin is a small protein, which is attached post-translationally to other proteins to regulate, amongst other things, their degradation, localisation and activity. A special feature of ubiquitin is its ability to form different types of polymers that mediate distinct functions.

So far, only a small subset of ubiquitin chains has been studied in detail, and cellular functions for the remaining ‘atypical’ chain types remain elusive. Importantly, the proteins that mediate assembly, binding and cleavage of ubiquitin chains are involved in a wide range of human diseases such as cancer, rheumatoid arthritis, and neurodegeneration.

David Komander and his team aim to unravel the complexity in the ubiquitin system and reveal the functions of atypical ubiquitin chains. Their work has led to the discovery of many proteins that assemble and disassemble ubiquitin polymers with remarkable linkage specificity, and the technologies and tools generated along the way have enabled research on previously unstudied ubiquitin polymers.

The group is focusing, in particular, on protein ubiquitination events in response to infection and inflammation, with the aim of understanding involved signalling cascades structurally and functionally. From this, much can be learned from pathogenic bacteria (including Salmonella, Yersinia, Escherichia and Legionella) that modulate ubiquitination cascades to fight the cellular response to infection. Studying the involved bacterial effector proteins may lead to identification of future drug targets.

Several patent applications have been filed relating to this technology. It is hoped that research in this area could eventually lead to new medicines to target key diseases such as cancer, diabetes, neurodegenerative disorders and a range of cardiovascular, metabolic, inflammatory and autoimmune diseases, as well as new classes of antibiotics.

In 2003 Millennium Pharmaceuticals won FDA approval for Velcade, an inhibitor of generalised proteasomal degradation. Although Velcade is the only drug targeting the ubiquitin-proteasome pathway that has reached the clinic, the pharmaceutical industry is showing strong interest in this area of research.