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
  • 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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