Pro-inflammatory signalling in cancer
We study molecular mechanisms governing pro-inflammatory signalling during innate immune responses. Through this, we aim to understand the molecular mechanisms that on one hand protect against pathogens, but that also contribute to chronic inflammation, tumor development and cancer progression. A central focus of the lab is to elucidate the role and regulation of non-degradative ubiquitin modifications in these processes. Ultimately, we aim to identify ubiquitin-handling factors that can be targeted to modulate inflammation and antagonize cancer.
The innate immune system relies on germ line-encoded pattern recognition receptors (PRRs), present on the cell surface and in the cytoplasm, that directly recognize molecular patterns of pathogens. Stimulation of bacteria-sensing PRRs leads to assembly of multi-protein complexes where ubiquitin ligases (E3s) and deubiquitinases assemble and disassemble polyubiquitin chains. In turn, these ubiquitin chains orchestrate activation of kinase signalling pathways, ultimately leading to an inflammatory response mediated by NF-κB transcription factors and transcription factors activated by MAP kinases. When correctly regulated, these processes drive appropriate and beneficial inflammation, resulting in efficient clearance of invading microbes. On the other hand, if they are/become deregulated, for example as a result of hereditary or somatic gene mutations or infection by pathogens, this may result in serious pathologies, including immunodeficiency, chronic inflammation and cancer.
Our recent work has focused on the role of Met1-linked ubiquitin chains (also known as linear ubiquitin chains) in inflammatory signaling. These chains are generated by the Linear UBiquitin Assembly Complex (LUBAC), which is a key component of inflammatory signaling pathways, including those activated downstream of the cytoplasmic PRRs NOD1 and NOD2 that serve as sensors for intracellular bacteria. We have uncovered and characterised several factors that regulate the function of LUBAC in signaling, including
- XIAP; a protein often overexpressed in human cancer and for which loss-of-function mutations give rise to the familial and often fatal immunodeficiency XLP2. We showed that XIAP recruits LUBAC to the NOD2-associated complex.
- OTULIN; a recently discovered deubiquitinase that specifically cleaves Met1-linked ubiquitin chains. We found that OTULIN binds to LUBAC and limits inflammatory signaling by NOD2.
- CYLD; a deubiquitinase and tumour suppressor for which familial loss-of-function mutations gives rise to tumours of skin appendages. We showed that CYLD associates with LUBAC and restrict conjugation of Met1-linked and Lys63-linked ubiquitin chains during inflammatory signaling.
Future work in the group will focus on elucidating the function, regulation and interplay of individual ubiquitin chain types (of which there are at least eight) during inflammatory signalling, with the aim to understand how the ubiquitin system ensures appropriate inflammatory responses