IMBA - Institute of Molecular Biotechnology GmbH, Dr. Bohr-Gasse 3, 1030 Vienna, Austria
Phone: +43 (0)1 79044-4900, Email: fumiyo.ikeda(at)imba.oeaw.ac.at
Ubiquitination in inflammation, cell death and autophagy
Our group studies how ubiquitin networks control inflammation, cell death and autophagy. We use multiple approaches to tackle this question, from biochemistry techniques to genetically modified animal models. Ubiquitin molecules link together to form chains with different topologies on their target proteins, depending on which enzymes link them together. These different topologies recruit distinct complexes and effectors that specifically regulate various aspects of physiology. We are particularly interested in understanding the mechanisms and biology of a non-classical topology: linear ubiquitination. Linear ubiquitin chains are essential regulators of multiple immune signalling cascades.
*Ebner, P., Poetsch, I., Deszcz, L., Hoffmann, T., Zuber, J., and Ikeda, F. (2018). The iap family member bruce regulates autophagosome-lysosome fusion. Nat Commun. 9(1):599.
*Asaoka, T., Almagro, J., Ehrhardt, C., Tsai, I., Schleiffer, A., Deszcz, L., Junttila, S., Ringrose, L., Mechtler, K., Kavirayani, A., Gyenesei, A., Hofmann, K., Duchek, P., Rittinger, K., Ikeda, F. (2016). Linear ubiquitination by LUBEL has a role in Drosophila heat stress response. EMBO Rep. 17(11):1624-1640
* Kumari, S., Redouane, Y., Lopez-Mosqueda, J., Shiraishi, R., Romanowska, M., Lutzmayer, S., Kuiper, J., Martinez, C., Dikic, I., Pasparakis, M., Ikeda, F. (2014). Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis. Elife. 3
Projects within VBC Ubiquitin Club
Mechanisms of linear ubiquitination by the LUBAC ligase complex
The LUBAC complex is the only known ubiquitin ligase complex capable of assembling these chains. However, it is unclear how LUBAC is regulated, activated, or recruited to signalling complexes. Furthermore, the mechanisms through which linear ubiquitin chains influence the activity of the substrates they are conjugated to are unknown.
Our group is using a multidisciplinary approach combining biochemistry, cellular and chemical biology to unravel the mechanisms underlying linear ubiquitination. We are specifically interested in understanding how linear ubiquitin chains mediate the activation of enzymatic substrates, and the mechanisms in regulating the activity of LUBAC. Through these studies, we aim to unravel the mechanistic role of linear ubiquitin chains in immune signalling and develop experimental strategies that can be universally applied to study ubiquitination.
In mammals, linear ubiquitination plays an important role in the immune responses and cell death. In mouse models in which LUBAC component is deficient, apoptosis is abnormally increased. While the involvement of LUBAC-dependent linear ubiquitination in the regulation of apoptosis and immune responses is clear, it remains to be understood how each LUBAC component regulates these events. Moreover, the roles of LUBAC in biology besides inflammatory responses and cell death remain largely elusive. We aim to understand the biological roles of linear ubiquitination using biochemical and cellular techniques coupled with genetically modified mouse models.
Recently, we identified the first linear ubiquitination enzyme in Drosophila melanogaster and named it LUBEL (linear ubiquitin E3 ligase). By introduction of mutations at the catalytic domain of LUBEL in flies, we established linear ubiquitin chain-deficient fly models, which enable us to explore the different aspects of linear ubiquitination in a whole organism. Our goal is to understand the fundamental biological functions of linear ubiquitination using a newly established fly model, especially the roles outside of inflammatory response.