Site-Selective Proximity-Synthetic Editors Rewrite p53 Acetylation to Dynamically Control Treg Lineage Differentiation 2307367

Abstract Introduction Regulatory T cells arise when CD4+ T cells commit to a regulatory fate, a process essential for immune tolerance and graft acceptance but whose failure drives autoimmunity; conversely, reinforcing this program in tumors enables immune evasion. Despite this bidirectional role, no pharmacological strategy can directly control Treg lineage commitment. p53, the guardian of the genome, integrates metabolic and chromatin signals via post-translational modifications, yet its role in CD4+ T-cell fate remains poorly understood. Methods We combined in silico modeling with biochemical acetylation assays and functional immunology approaches. Lysine-selective p53 acetylation was examined using genetic and pharmacological tools. We engineered first-in-class Proximity-Synthetic Editors (PSEs), bifunctional small molecules linking a cell-penetrant p53-binding peptide to selective TIP60 or p300 activators. Treg differentiation and function were assessed in vitro and in vivo in cardiac allograft and experimental autoimmune encephalomyelitis models. Results We identify a binary p53 acetylation logic governing Treg lineage fate. TIP60-mediated acetylation of p53 at K120 is required for efficient Treg induction, whereas p300-driven C-terminal acetylation at K373—382 suppresses Treg differentiation. TIP60-directed PSEs enforce K120 acetylation, promoting Foxp3 expression and Treg differentiation, resulting in prolonged allograft survival and ameliorated EAE. Conversely, p300-directed PSEs inhibit Treg differentiation, accelerate graft rejection, and exacerbate EAE scores. Conclusion These findings define p53 acetylation as a decisive molecular code governing Treg lineage commitment and demonstrate that proximity-induced pharmacology enables direct, reversible, and site-selective control of intracellular fate decisions. By enabling bidirectional manipulation of immune tolerance with small molecules, this platform establishes a new paradigm for precision immunomodulation across autoimmunity and organ transplantation. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)