2026 Volume 41 Issue 2 Pages 106-114
Targeted protein degradation has recently emerged as a new therapeutic modality that exploits the ubiquitin–proteasome system. Major classes of degrader molecules, such as PROTACs and molecular glues, function by bringing a target protein (neo-substrate) into close proximity with an E3 ubiquitin ligase, thereby enforcing ubiquitination of the target and inducing its proteasome-dependent degradation. Consequently, a detailed understanding of degradation mechanisms based on the fundamental principles of the ubiquitin–proteasome system is essential for improving the efficiency and precision of targeted protein degradation. In recent years, the importance of higher-order architectures of ubiquitin chains, referred to as the ubiquitin code, in promoting protein degradation has become increasingly evident. In this article, we first outline the basic principles of the ubiquitin–proteasome system and the concept of the ubiquitin code, and then discuss intracellular regulatory factors that control targeted protein degradation and the mechanisms by which these factors promote degradation, including insights from our own work.
