My research focuses on understanding how innate immune signalling is regulated, and how it impacts on inflammation and cancer. My main interests lie with the function and regulation of the ubiquitin system in these processes, with emphasis on delineating the non-degradative functions of ubiquitin chains.
I studied Biochemistry at the University of Copenhagen and carried out my PhD at the Danish Cancer Society Research Centre on the topic of cell death and cancer. My interest in ubiquitin began as a postdoctoral fellow at the Institute of Cancer Research in London. Here, my colleagues and I discovered that Inhibitor of Apoptosis (IAP) proteins interact with ubiquitin through a conserved ubiquitin-binding module. We demonstrated that this module contributes to the immune regulatory activity of these proteins and that it is important for their oncogenic potential.
As head of my own research team since 2011, I have studied how ubiquitin controls signalling downstream of innate immune receptors such as NOD2 - a bacteria-sensing receptor central for maintaining an immunological barrier in the gastrointestinal tract, and for which loss-of-function mutations predispose to inflammatory bowel disease (IBD), a condition that increases the risk of intestinal cancer. Our work has contributed to understanding the ubiquitin-dependent processes that control NOD2 signalling, including identifying X-linked IAP (XIAP) as an essential ubiquitin ligase for NOD2 signalling. More recently, our work has uncovered that signalling mediated by the linear ubiquitin chain assembly complex (LUBAC), a ubiquitin ligase that mediates signalling by most immune receptors, is regulated by the deubiquitinases OTULIN and SPATA2-CYLD.
In October 2013, I moved to the Ludwig Cancer Research Oxford Branch to combine our work on the basic concepts of ubiquitin-mediated signalling with the role of these processes in cancer development and progression.
Our research aims to understand how ubiquitin chains contribute to inflammatory signalling triggered in response to infection and by cytokines in the tumour microenvironment. Chronic or unresolved inflammation is an enabling characteristic of cancer and infections are estimated to account for 1 in 6 of all malignancies. Therefore, understanding the basic mechanisms controlling innate immune signalling, will advance our understanding of the interplay between inflammation and cancer, and has the potential to reveal molecular targets for novel treatment strategies.
Ubiquitin can be assembled in eight different ways by the ubiquitin system to create different types of ubiquitin chains that constitute unique signals in the cell: Lys63- and Met1-linked ubiquitin chains, in particularly, play an important role in innate immune signalling and inflammation. Current questions we are addressing include:
- How is the Met1-linked ubiquitin conjugating machinery regulated?
- What is the function of different ubiquitin chains in inflammatory signalling?
- How do ubiquitin chains influence inflammatory responses in the tumour microenvironment?
Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling.
Hrdinka M. et al, (2018), EMBO J, 37
SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUBAC Signaling.
Elliott PR. et al, (2016), Mol Cell, 63, 990 - 1005
CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling.
Hrdinka M. et al, (2016), Cell Rep, 14, 2846 - 2858
Molecular basis and regulation of OTULIN-LUBAC interaction.
Elliott PR. et al, (2014), Mol Cell, 54, 335 - 348
The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity.
Damgaard RB. et al, (2012), Mol Cell, 46, 746 - 758
HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection.
Bodda C. et al, (2020), The Journal of experimental medicine, 217
Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling
Fenech EJ. et al, (2020)
Ubiquitin signalling in inflammation
Gyrd-Hansen M., (2019), FEBS OPEN BIO, 9, 9 - 9