Controllable targeted protein degradation as a promising tool for discovery of novel cellular and developmental mechanisms

Abstract

Studying the spatial and temporal roles of essential proteins remains technically challenging. The effectiveness of perturbing gene functions using well established approaches upstream of the protein level, such as conditional knockout and RNA interference or morpholino-mediated knockdown, are often dependent upon the turnover rate of pre-existing proteins. Acute targeted protein degradation technologies can circumvent this limitation, and has emerged as powerful tools for discoveries of previously unrecognized protein functions in highly dynamic cellular and developmental processes. Auxin-inducible degron, degrade green fluorescent protein, degradation tag and proteolysis-targeting chimera are efficient for rapid knockdown of degron-tagged or untagged endogenous proteins in a controllable manner. All these approaches harness the evolutionarily conserved multi-protein E3 ubiquitin ligase complex in targeting proteins for degradation by the proteasome, offering versatile applications for protein functional studies in yeasts, plants, invertebrates, and vertebrates. This review presents the understanding of spatial and temporal protein functions advanced by commonly used auxin-inducible degron, degrade green fluorescent protein and degradation tag technologies. It also mentions the promising therapeutic potentials offered by the proteolysis-targeting chimera. With constant improvements, targeted protein degradation will open up new avenues for unprecedented findings of the dynamic features in a living system.