Targeted Protein Degradation by Repurposing Transmembrane E3 Ubiquitin Ligases

Targeted protein degradation (TPD) is an emerging therapeutic strategy that leverages the cell's native degradation machinery to eliminate disease-causing proteins. An advanced approach in this field operates by mediating proximity-induced ubiquitination between E3 ubiquitin ligases and proteins of interest, thereby triggering their proteasomal destruction. Recent advances have expanded this paradigm to cell-surface proteins, opening a new frontier in targeting the undrugged proteome. This review highlights the development of TPD technologies that exploit cell-surface E3 ligases for the degradation of membrane proteins.