2026-01-29 東京大学
図1:タンパク質を間接的にユビキチン化する
<関連情報>
- https://www.t.u-tokyo.ac.jp/press/pr2026-01-29-003
- https://www.t.u-tokyo.ac.jp/hubfs/press-release/2026/0129/003/text.pdf
- https://www.nature.com/articles/s42004-026-01895-x
標的タンパク質分解のための内因性ユビキチン化機構に依存しない間接ユビキチン化 Indirect ubiquitination independent of endogenous ubiquitination machinery for targeted protein degradation
Takafumi Furuhata,Kazuki Yoshida,Ryoka Fujita,Jotaro Miyamoto,Chiharu Moriyama,Tokiha Masuda-Ozawa,Hikaru Tsuchiya,Yasushi Saeki & Akimitsu Okamoto
Communications Chemistry Published:29 January 2026
DOI:https://doi.org/10.1038/s42004-026-01895-x
Abstract
Heterobifunctional small degrader molecules that hijack endogenous E3 ubiquitin ligases have attracted attention for the rapid and irreversible knock-down of target proteins via ubiquitination. However, the formation of appropriately oriented E3 ligase–target complexes is required for efficient ubiquitination of the target, which complicates the molecular optimization and leads to acquired drug resistance caused by the loss of E3 ligase activity and mutations at the E3–target interfaces. Here, we report on indirect ubiquitination as a chemical strategy for E3-indepedent ubiquitin-tethering to the target substrate. Comprising a ligand molecule and a ubiquitin moiety, the designed chimeric molecule enables the ubiquitination of the target proteins via non-covalent interactions, which lead to the proteasomal degradation of recombinant Bcl-2 and NF-κB p50, and intracellular endogenous Bcl-2. Indirect ubiquitination offers a design platform for non-covalent tethering of a ubiquitin-based proteolytic modifier to be added in the molecular toolbox for the targeted protein degradation.
