Small-molecule TIP60 inhibitors enhance regulatory T cell induction through TIP60-P300 acetylation crosstalk Fueyo-González, Francisco Vilanova, Guillermo Ningoo, Mehek Marjanovic, Nada González Vera, Juan Antonio Orte Gutiérrez, Ángel Fribourg, Miguel Foxp3 acetylation is essential to regulatory T (Treg) cell stability and function, but pharmacologically increasing it remains an unmet challenge. Here, we report that small-molecule compounds that inhibit TIP60, an acetyltransferase known to acetylate Foxp3, unexpectedly increase Foxp3 acetylation and Treg induction. Utilizing a dual experimental/computational approach combined with a newly developed FRET-based methodology compatible with flow cytometry to measure Foxp3 acetylation, we unraveled the mechanism of action of these small-molecule compounds in murine and human Treg induction cell cultures. We demonstrate that at low-mid concentrations they activate TIP60 to acetylate P300, a different acetyltransferase, which in turn increases Foxp3 acetylation, thereby enhancing Treg cell induction. These results reveal a potential therapeutic target relevant to autoimmunity and transplant. 2024-04-10T11:36:27Z 2024-04-10T11:36:27Z 2023-11-19 journal article Fueyo-González et al., iScience 26, 108491 December 15, 2023 [10.1016/j.isci.2023.108491] https://hdl.handle.net/10481/90614 10.1016/j.isci.2023.108491 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier