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
Affiliations
Francisco Fueyo-González
Translational Transplant Research Center, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Guillermo Vilanova
LaCàN, Universitat Politècnica de Catalunya-BarcelonaTech, 08034 Barcelona Spain
Mehek Ningoo
Translational Transplant Research Center, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Nada Marjanovic
Deparment of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Juan A. González-Vera
Deparment of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; 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
Ángel Orte
Deparment of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; 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
Miguel Fribourg
Translational Transplant Research Center, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Corresponding author
Summary: 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.
