Shin-biology regulated by protein lifetime

Grant-in-Aid for Transformative Research Areas (A) FY2023–FY2027, MEXT Japan


We aim to solve this bottleneck by establishing large-scale protein lifetime measurement methods and manipulation techniques to achieve Shin-biology.

Proteins are essential functional elements of living organisms, and the functions of cells and tissues are determined by the proteome, which consists of tens of thousands of different types of proteins. Proteins are synthesized based on genetic information, but the correlation between the amount of mRNA and translation and the amount of protein is low, and post-translational regulation, especially by proteolysis, is essential. Individual proteins have different lifetimes, ranging from a few minutes to several years. Several laws have been proposed to determine protein lifetime. Still, while they can explain the lifetime of some proteins, they do not understand the lifetime of most proteins, and the mechanism by which proteins determine their lifetime after they are produced remains unclear. In addition, the regulation of the lifetime of individual proteins has been extensively studied in critical biological phenomena, but these studies observe only a very limited aspect of protein dynamics. For example, the protein composition must be drastically reconfigured when a cell undergoes a major functional transformation. In such cases, protein degradation also changes dynamically along with changes in protein synthesis. However, the mechanisms by which selective and large-scale proteolysis occurs on a time axis in various biological phenomena and pathological conditions are unknown.

To unravel these mysteries, we will explore new fundamental principles of protein lifetime regulation, establish techniques to measure protein lifetimes in-depth and elucidate the protein lifetime regulation mechanisms that drive large-scale changes in protein composition under various physiological and pathological conditions. We will also explore the factors that regulate protein lifetime by integrating protein sequence information, post-translational modification information, and predicted 3D structures. In addition, we will develop new technologies to freely control protein lifetime and establish methods to manipulate cellular and tissue functions and pathological conditions. As described above, this research area brings together researchers in proteolysis, analytical chemistry, informatics, and chemical biology to "understand," "measure," and "manipulate" the mechanisms of protein lifetime to achieve a "shin" (new/authentic/deep) understanding of biological phenomena and pathological conditions regulated by protein lifetime.