Small-molecule TIP60 inhibitors enhance regulatory T cell induction through TIP60-P300 acetylation crosstalk

Francisco Fueyo-González; Guillermo Vilanova; Mehek Ningoo; Nada Marjanovic; Juan A González-Vera; Ángel Orte; Miguel Fribourg

doi:10.1016/j.isci.2023.108491

Small-molecule TIP60 inhibitors enhance regulatory T cell induction through TIP60-P300 acetylation crosstalk

iScience. 2023 Nov 19;26(12):108491. doi: 10.1016/j.isci.2023.108491. eCollection 2023 Dec 15.

Authors

Francisco Fueyo-González^{1

2}, Guillermo Vilanova³, Mehek Ningoo^{1

2}, Nada Marjanovic⁴, Juan A González-Vera^{4

5}, Ángel Orte^{4

5}, Miguel Fribourg^{1

2}

Affiliations

¹ Translational Transplant Research Center, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
² Immunology Institute Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³ LaCàN, Universitat Politècnica de Catalunya-BarcelonaTech, 08034 Barcelona Spain.
⁴ Deparment of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁵ Nanoscopy-UGR Laboratory, Departamento de Fisicoquímica, Unidad de Excelencia de Química Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain.

Abstract

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.

Keywords: Immunology; Molecular biology.

Abstract

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