Analysis of protein lifetime regulation by TRIM ubiquitin ligases
Professor, Faculty of Medicine and Graduate School of Medicine, Hokkaido University
https://hokudai-ikagaku.jp/en/
researchmap: https://researchmap.jp/shigetsuguhatakeyama
There are approximately 70 TRIM family proteins in humans and TRIM proteins are known to be important in various biological functions and pathogenesis. TRIM proteins are involved in the regulation of both proteasome-dependent and autophagy-mediated protein degradation, which are important for intracellular “protein lifetime.” In this study, we use proteomics analysis that can identify ubiquitinated substrates with high sensitivity and specificity to comprehensively analyze the relationship between lifetime and the related diseases of important proteins in biological functions involving TRIM proteins. Furthermore, based on the results of this study, we elucidate the molecular mechanism of disease onset (immune/inflammatory diseases and cancer) and apply it to clinical medicine (drug discovery application to disease-specific biomarkers and PROTAC). In addition, by using the TUBE-E3 method established by us, we establish an off-target evaluation system for PROTAC and contribute to the development of a safety evaluation system for drug discovery.
- Kasuga Y., Ouda R., Watanabe M., Sun X., Kimura M., Hatakeyama S., & Kobayashi K. S. (2023) FBXO11 constitutes a major negative regulator of MHC class II through ubiquitin-dependent proteasomal degradation of CIITA. Proceedings of the National Academy of Sciences. 10.1073/pnas.2218955120
- Inoue A., Watanabe M., Kondo T., Hirano S., & Hatakeyama S. (2022) TRIM22 negatively regulates MHC-II expression. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1869, 119318
- Watanabe M., Saeki Y., Takahashi H., Ohtake F., Yoshida Y., Kasuga Y., Kondo T., Yaguchi H., Suzuki M., Ishida H., Tanaka K., & Hatakeyama S. (2020) A substrate-trapping strategy to find E3 ubiquitin ligase substrates identifies Parkin and TRIM28 targets. Commun Biol. 3, 592
- Sugawara E., Kato M., Kudo Y., Lee W., Hisada R., Fujieda Y., Oku K., Bohgaki T., Amengual O., Yasuda S., Onodera T., Hatakeyama S., & Atsumi T. (2020) Autophagy promotes citrullination of VIM (vimentin) and its interaction with major histocompatibility complex class II in synovial fibroblasts. Autophagy. 16, 946–955
- Hatakeyama S. (2017) TRIM Family Proteins: Roles in Autophagy, Immunity, and Carcinogenesis. Trends Biochem Sci. 42, 297–311