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Our research aims to understand how the ubiquitin system contributes to innate immune signalling triggered by bacterial pathogens and cytokines, with a particular focus on the signalling properties of ubiquitin modifications in the context of NF-κB-dependent inflammation and within the tumour microenvironment (TME).

 

A schematic of the main research in the Gyrd-Hansen lab. Microbes and cytokines are recognised by pattern recognition receptors and cytokine receptors respecitvely. This initiations a signalling cascade mediated by E3 ubiquitin ligases that catalyse the addition of 8 types of ubiquitin chains onto substrate proteins. Deubiquitinases catalyse the breakdown of these chains. The ubiquitin signalling system causes transcriptional induction of inflammatory mediators via the transcription factors AP-1 and NK-kappaB to trigger inflammation.

Chronic or unresolved inflammation is an enabling characteristic of cancer and infections are estimated to account for 1 in 6 of all malignancies. Understanding the basic regulatory mechanisms controlling innate immune signalling, such as ubiquitination, will advance our understanding of the interplay between inflammation, the TME 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. Several of these contribute to innate immune signalling and inflammatory responses but the role and regulation of most ubiquitin chain types, collectively termed atypical ubiquitin chains, remains poorly understood. My group’s research aims to uncover how the ubiquitin system regulates these processes, with a particular focus on the signalling property of ubiquitin in myeloid cells.

 

Key questions we are addressing include:

How is the Met1-linked ubiquitin conjugating machinery regulated? 

What is the function of atypical ubiquitin chains in inflammatory signalling?

How does ubiquitin signalling influence inflammatory responses in the TME?