Multifaceted targeted protein degradation systems for different cellular compartments

Abstract

Selective protein degradation maintains cellular homeostasis, but this process is disrupted in many diseases. Targeted protein degradation (TPD) approaches, built upon existing cellular mechanisms, are promising methods for therapeutically regulating protein levels. Here, we review the diverse palette of tools that are now available for doing so throughout the gene expression pathway and in specific cellular compartments. These include methods for directly removing targeted proteins via the ubiquitin proteasome system with proteolysis targeting chimeras (PROTACs) or dephosphorylation targeting chimeras (DEPTACs). Similar effects can also be achieved through the lysosomal system with autophagy‐targeting chimeras (AUTACs), autophagosome tethering compounds (ATTECs), and lysosome targeting chimeras (LYTACs). Other methods act upstream to degrade RNAs (ribonuclease targeting chimeras; RIBOTACs) or transcription factors (transcription factor targeting chimeras; TRAFTACs), offering control throughout the gene expression process. We highlight the evolution and function of these methods and discuss their clinical implications in diverse disease contexts.

Intrahippocampal injection of IL‐1β upregulates Siah1‐mediated degradation of synaptophysin by activation of the ERK signaling in male rat

“…There are two common pathways for protein degradation in eukaryotes: one is the ubiquitin proteasome system action, and the other is mediated by lysosome (Varshavsky, 2017; Zorca et al, 2022). Many experimental studies have emphasized the important role of ubiquitin in setting protein fate.…”