Welcome to the Ikeda lab
We are interested in ubiquitin - a fascinating post-translational modification that is essential for a variety of biological functions, including a proper immune response. Various enzymes generate different types of ubiquitin chains. This topological complexity leads to diverse protein functions that influence various biological processes. Ubiquitin chains can form eight different linkage types with the intrinsic seven lysine (Lys) residues or the single initiating methionine (Met 1). Among the eight linkage types, we are particularly interested in a non-classical type of chain, the linear ubiquitin chain. These chains look like “pearls-on-a-string”, with the C-terminal of a distal ubiquitin linked to the Met 1 residue of a proximal ubiquitin. Compared to the classical Lys-linked ubiquitin chains, linear ubiquitin chains have unique biochemical and structural properties. The biological importance of linear ubiquitination is not yet fully understood.
As a DDS (Doctor in Dental Surgery)-PhD, I have been fascinated by how the stress response in our body is regulated. Since the start of my scientific career, I have been driven to work on cell signaling to elucidate the regulatory mechanisms underlying inflammatory responses, in which protein ubiquitination plays a critical role. During my postdoctoral studies, I made a major contribution with the discovery of linear ubiquitination in the regulation of cell death and inflammation in mammals. Now we have developed interests in the connection between inflammation, cell death and autophagy, which is dependent on ubiquitination. The vision of our research is to understand the regulatory mechanism of stress responses. We reach our aims in a multidisciplinary way, without hesitating to use any required methods or approaches.
We are interested in a specific ubiquitin E3 ligase complex, the Linear Ubiquitin Chain Assembly Complex (LUBAC), which is critical for a proper immune response in people. LUBAC generates linear ubiquitin chains that impact the fates of its substrates in a specific, but poorly understood manner. We aim to understand how linear ubiquitination affects its target proteins and, ultimately, cellular responses.
To understand how inflammation, cell death, and autophagy are regulated by linear ubiquitination, we focus on the enzymes for linear ubiquitination and their substrates, and aim to elucidate how the ubiquitin modification affects cell signaling responses. We use techniques in molecular biology and biochemistry in general, including mass spectrometry, as well as various cell signaling assays, such as FACS and confocal microscopy. To elucidate the biological relevance of linear ubiquitination in vivo, we use genetically-modified animal models (mouse and fly) and examine the stress response phenotypes in vivo and as well as cellular responses ex vivo.
The biological importance of LUBAC (Linear Ubiquitin Chain Assembly Complex)
LUBAC is thus far the only ligase known to generate linear ubiquitin chains. LUBAC consists of 3 proteins (HOIP, HOIL-1L and Sharpin), all of which are important for the adaptive immune signaling cascade, namely TNF-induced NF-kB activation, cell death and autophagy. Mutations in HOIP and HOIL-1 are associated with autoimmune disease as well as myopathy in humans. In mice, knockout of HOIP and HOIL-1L leads to embryonic lethality, whereas Sharpin-deficient mice suffer from systemic inflammation. In addition, the homologous Linear Ubiquitin E3 Ligase (LUBEL) in flies regulates heat tolerance. We use mouse and fly models to understand how these biological functions are regulated by the linear ubiquitination enzymes/complexes.
Since essential enzymes regulating linear ubiquitination were found to be important for proper immunity and to control cancer development in humans, it is critical to understand how linear ubiquitination is regulated and how linear ubiquitination impacts diverse cellular responses. Our research is expected to contribute to the development of therapeutic strategies that correct or manipulate protein ubiquitination.
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
Ikeda, F., Deribe, YL., Skånland, SS., Stieglitz, B., Grabbe, C., Franz-Wachtel, M., van Wijk, SJ., Goswami, P., Nagy, V., Terzic, J., Tokunaga, F., Androulidaki, A., Nakagawa, T., Pasparakis, M., Iwai, K., Sundberg, JP., Schaefer, L., Rittinger, K., Macek, B., Dikic, I. (2011). SHARPIN forms a linear ubiquitin ligase complex regulating NF-?B activity and apoptosis. Nature. 471(7340):637-41
Ikeda, F., Crosetto, N., Dikic, I. (2010). What determines the specificity and outcomes of ubiquitin signaling? Cell. 143(5):677-81
Rahighi, S., Ikeda, F., Kawasaki, M., Akutsu, M., Suzuki, N., Kato, R., Kensche, T., Uejima, T., Bloor, S., Komander, D., Randow, F., Wakatsuki, S., Dikic, I. (2009). Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell. 136(6):1098-109