Strategies for Post-Translational Control of Protein Expression and Their Applications

Abstract

Proteins are fundamental biomolecules of living cells, and their expression levels depend on the balance between the synthesis and degradation. Researchers often aim to control protein expression levels for the investigation of protein function and its relationship with physiological phenomena. The genetic manipulation of the target protein using CRISPR/Cas9, Cre/loxP, tetracyclin system, and RNA interference, are widely used for the regulation of proteins at the DNA, transcriptional, or mRNA level. However, the significant time delay in controlling protein levels is a limitation of these techniques; the knockout or knockdown effects cannot be observed until the previously transcribed and synthesized protein is degraded. Recently, researchers have developed various types of molecular tools for the regulation of protein expression at the post-translational level, which rely on harnessing cellular proteolytic machinery including ubiquitin–proteasome pathway, autophagy-lysosome pathway, and endocytosis. The post-translational control of protein expression using small molecules, antibodies, and light can offer significant advantages regarding speed, tunability, and reversibility. These technologies are expected to be applied to pharmacotherapy and cell therapy, as well as research tools for fundamental biological studies. Here, we review the established and recently developed technologies, provide an update on their applications, and anticipate potential future directions.

Keywords

• targeted protein degradation
• protein knockdown
• chemical knockdown
• degron
• conditional knockdown