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Research Overview

Welcome to the Ikeda lab website. 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 (Figure 1). 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.

Figure 1. Linear ubiquitin chain.

Vision

As a DDS (Doctor in Dental Surgery)-PhD, Fumiyo Ikeda has been fascinated by how the stress response in our body is regulated. Since the start of her scientific career, she has been driven to work on cell signaling to elucidate the regulatory mechanisms underlying inflammatory responses, in which protein ubiquitination plays a critical role. During her postdoctoral studies, she made a major contribution with the discovery of linear ubiquitination in the regulation of cell death and inflammation in mammals. Now she has developed interests in the connection between inflammation, cell death and autophagy, which is dependent on ubiquitination. The vision of her research is to understand the regulatory mechanism of stress responses. Her team reaches the aims in a multidisciplinary way, without hesitating to use any required methods or approaches.

Mission

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. We use molecular and biochemical tools that we have developed, as well as animal models.

Approach

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 examine the stress response phenotypes in vivo and as well as cellular responses ex vivo.