Researchers from the CAMS Oxford Institute and NDM Target Discovery Institute, including Prof Benedikt Kessler and Dr Adán Pinto-Fernández, have collaborated with the team of Dr Paul Geurink and Dr Aysegul Sapmaz from Leiden University to investigate an important interferon-stimulated gene, ISG15.
The innate immune system serves as a first line of defence against viral and bacterial infections in mammalian cells. Activation of this system initiates the release of Type-I interferons (mainly IFN-a and IFN-b), which eventually leads to the transcription of more than 300 interferon-stimulated genes (ISGs). These ISGs encode different proteins, such as cytokines, chemokines, transcription factors, and enzymes that regulate the host immune response. One of the most strongly induced proteins is ISG15 which binds to many other important proteins to alter their function.
In this study, the researchers from Leiden University and Oxford University discovered for the first time that the ubiquitin specific protease family member, USP16, can remove ISG15 from proteins in addition to the previously discovered USP5 & USP18. The proteins which USP16 removes ISG15 from are involved in the metabolism of the cell and gluconeogenesis, the synthesis of new glucose from non-carbohydrate precursors. USP16 antagonists could, therefore, have potential as therapeutic targets for immunometabolic diseases.
The study was conducted using cutting-edge mass spectrometry-based techniques. CAMS Oxford Institute Career Development Fellow, Dr Adán Pinto-Fernández shares his thoughts on the importance of the study: 'This study highlights how Ubiquitomics and Proteomics workflows, such as Activity-based Protein Profiling and Interactomics, helped uncovering a new ISG15-processing enzyme called USP16 and its cellular substrates. This discovery opens up exciting possibilities for finding a target that can be treated with drugs, offering potential benefits for cancer treatment.'
Read the full article, published in The Proceedings of the National Academy of Sciences (PNAS), here.