Targeted Protein Acetylation in Cells Using Heterobifunctional Molecules

Protein acetylation is a central
event in orchestrating diverse
cellular processes. However, current strategies to investigate protein
acetylation in cells are often nonspecific or lack temporal and magnitude
control. Here, we developed an acetylation tagging system, AceTAG,
to induce acetylation of targeted proteins. The AceTAG system utilizes
bifunctional molecules to direct the lysine acetyltransferase p300/CBP
to proteins fused with the small protein tag FKBP12F36V, resulting in their induced acetylation. Using AceTAG, we induced
targeted acetylation of a diverse array of proteins in cells, specifically
histone H3.3, the NF-κB subunit p65/RelA, and the tumor suppressor
p53. We demonstrate that targeted acetylation with the AceTAG system
is rapid, selective, reversible and can be controlled in a dose-dependent
fashion. AceTAG represents a useful strategy to modulate protein acetylation
and should enable the exploration of targeted acetylation in basic
biological and therapeutic contexts.