Research

Inflammation is the body’s normal, protective response to infection or tissue damage. Appropriate control of inflammation is critical for maintaining tissue homeostasis and for mounting prompt responses to infectious pathogens. When correctly regulated, inflammation is a beneficial response, resulting in clearance of the infectious agent and tissue repair. In contrast, if the regulatory mechanisms fail, dysregulated or uncontrolled inflammation may ensue, which can cause chronic inflammatory disease, immunodeficiency, and lead to development of cancer.

A particular focus in the lab is how the ubiquitin system controls and coordinates the pro-inflammatory signalling. Ubiquitination is the post-translational conjugation of the small protein ubiquitin to substrates. This signalling mechanism regulates virtually all cellular processes and it is particularly critical for initiating and coordinating inflammatory signalling.

The regulatory versatility of ubiquitination arises from the formation of a signalling code comprised of eight different types of ubiquitin polymers, called ubiquitin chains: Lys6-, Lys11-, Lys27, Lys29, Lys33, Lys48, Lys63, and Met1-linked ubiquitin chains. Dedicated “writers” (ubiquitin ligases) build the code, “readers” (ubiquitin receptors) decode it and funnel substrates into biological pathways, and “erasers” (deubiquitinases) erase the code and reset the signalling circuit.

In response to an inflammatory stimulus, e.g. an infection, pattern-recognition receptors and other germ line-encode receptors of the innate immune system employ a host of ubiquitin ligases, ubiquitin receptors, and deubiquitinases to orchestrate the activation of kinase-dependent signalling cascades that ultimately results in activation of the transcription factors NF-kB and AP-1 that drive the inflammatory response.

Using a combination of molecular cell biology, biochemistry, and mass spectrometry-based proteomics, the lab studies the ubiquitin-dependent mechanisms that control pro-inflammatory signalling and how this signalling is integrated with other cellular pathways, e.g. cell death and metabolism, to control and tune the inflammatory response.

Our long-term goal is to identify molecular processes that can be targeted pharmacologically to treat cancer and other diseases caused by chronic or dysregulated inflammation.

The Ubiquitin Signalling and Inflammation group is funded by a Hallas-Møller Emerging Investigator Grant in Bioscience and Basic Biomedicine from the Novo Nordisk Foundation.

Main projects and aims in the lab

• Understand how inflammatory signalling processes are controlled by the ubiquitin system
• Investigate ubiquitin signalling mechanisms in molecular detail as well as at a global scale in cells and tissues using omics technologies
• Develop tools and experimental techniques to investigate the function of specific ubiquitin chain types in signalling

Selected publications for further reading

Damgaard RB*, Jolin HE, Allison MED, Davies SE, Titheradge HL, McKenzie ANJ, and Komander D*. “OTULIN protects the liver against cell death, inflammation, fibrosis, and cancer.” Cell Death & Differentiation (2020).

Damgaard RB, Elliott PR, Swatek K, Maher ER, Stepensky P, Elpeleg O, Komander D, and Berkun Y. “OTULIN deficiency in ORAS causes cell type‐specific LUBAC degradation, dysregulated TNF signalling and cell death.” EMBO Molecular Medicine 11 e9324 (2019).

Damgaard RB, Walker JA, Marco-Casanova P, Morgan NV, Titheradge HL, Elliott PR, McHale D, Maher ER, McKenzie ANM, and Komander D. “The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity.” Cell166 (5), 1215-1230 (2016).

Damgaard RB, Fiil BK^#, Speckmann C, Yabal M, zur Stadt U, Bekker-Jensen S, Jost PJ, Ehl S, Mailand N, and Gyrd-Hansen M. “Disease‐causing mutations in the XIAP BIR2 domain impair NOD2‐dependent immune signaling.” EMBO Molecular Medicine 5 (8), 1278-1295 (2013).

Fiil BK, Damgaard RB, Wagner SA, Keusekotten K, Fritsch M, Bekker-Jensen S, Mailand N, Choudhary C, Komander D, and Gyrd-Hansen M. “OTULIN Restricts Met1-Linked Ubiquitination to Control Innate Immune Signaling.” Molecular Cell 50 (6), 818-830 (2013).

Damgaard RB, Nachbur U, Yabal M, Wong WW-L, Fiil BK, Kastirr M, Rieser E, Rickard J, Bankovacki A, Peschel C, Ruland J, Bekker-Jensen S, Mailand, M, Kaufmann T, Strasser A, Walczak H, Silke J, Jost PJ, and Gyrd-Hansen M. “The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity.” Molecular Cell 46 (6), 746–758 (2012).