2. Academic Validation
  3. Small-molecule TIP60 inhibitors enhance regulatory T cell induction through TIP60-P300 acetylation crosstalk

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.
Francisco Fueyo-González 1 2,  Guillermo Vilanova 3,  Mehek Ningoo 1 2,  Nada Marjanovic 4,  Juan A González-Vera 4 5,  Ángel Orte 4 5,  Miguel Fribourg 1 2
Affiliations

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.
PMID: 38094248 DOI: 10.1016/j.isci.2023.108491
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.

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