Ubiquitin and ubiquitin-like proteins in the immune system

The posttranslational modification of proteins is a fundamental process in all organisms.

For instance, ubiquitin and ubiquitin-like protein modifications play critical roles in virtually all aspects of eukaryotic biology, including protein degradation, cell division, and immunity.

These are dynamic, tightly controlled and highly tunable processes; therefore, misregulation of the enzymes and proteins involved in these signalling pathways is associated with many diseases.

Thus, understanding how these modifications regulate cell signalling pathways is fundamentally important to human health.

The objective of my laboratory is to discover the mechanisms underpinning how the ubiquitin-like protein, interferon-stimulated gene 15 (ISG15), contributes to the host immune system. ISG15 is a ubiquitin-like protein that functions in the innate immune response. During viral infection, a sharp rise in ISG15 production modifies thousands of proteins to defend the host cell.

Moreover, many pathogenic viruses, including coronaviruses, have evolved mechanisms to remove and redirect these modifications to subvert ISG15 signalling. Accumulating evidence strongly supports these signals serve distinct and important biological roles. However, the function of most ISG15 modifications remains unknown.

Therefore, my laboratory aims to advance ISG15 research by focusing on several key priority areas. 1) To understand the molecular details of ISG15 substrate recognition and targeting 2) To identify ISG15 substrates and define their functions 3) To reveal new viral strategies to evade ISG15 signalling 4) To develop state-of-the-art technologies to study ISG15 My laboratory takes a multidisciplinary and collaborative approach to science using proteomics, structural biology, biochemistry, biophysics, chemical biology, and cell biology to answer our questions.

The MRC PPU is ideal for undertaking this research due to recent investments in single-particle cryo-EM, high-end mass spectrometry, and existing expertise in ubiquitin biology, chemical biology, and immune signalling at the University.

Together, I am confident that the collaborative and supportive environment here will facilitate progress in my research.

The ubiquitin field has made great strides in deciphering the biological roles of ubiquitin and some ubiquitin-like proteins.

I anticipate our efforts on the understudied and enigmatic ubiquitin-like protein ISG15 will similarly reveal fascinating new insights and unlock unexpected and important biological functions related to human health and disease.