Dynamic interactions between TIP60 and p300 regulate FOXP3 function through a structural switch defined by a single lysine on TIP60

Cell Rep. 2014 Jun 12;7(5):1471-1480. doi: 10.1016/j.celrep.2014.04.021. Epub 2014 May 15.


The human FOXP3 molecule is an oligomeric transcriptional factor able to mediate activities that characterize T regulatory cells, a class of lymphocytes central to the regulation of immune responses. The activity of FOXP3 is regulated at the posttranslational level, in part by two histone acetyltransferases (HATs): TIP60 and p300. TIP60 and p300 work cooperatively to regulate FOXP3 activity. Initially, p300 and TIP60 interactions lead to the activation of TIP60 and facilitate acetylation of K327 of TIP60, which functions as a molecular switch to allow TIP60 to change binding partners. Subsequently, p300 is released from this complex, and TIP60 interacts with and acetylates FOXP3. Maximal induction of FOXP3 activities is observed when both p300 and TIP60 are able to undergo cooperative interactions. Conditional knockout of TIP60 in Treg cells significantly decreases the Treg population in the peripheral immune organs, leading to a scurfy-like fatal autoimmune disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autoimmune Diseases / metabolism
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • HEK293 Cells
  • Histone Acetyltransferases / chemistry
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism*
  • Humans
  • Lysine / metabolism
  • Lysine Acetyltransferase 5
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Protein Binding
  • T-Lymphocytes, Regulatory / metabolism
  • Trans-Activators / chemistry
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*


  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Trans-Activators
  • E1A-Associated p300 Protein
  • Histone Acetyltransferases
  • Kat5 protein, mouse
  • Lysine Acetyltransferase 5
  • Lysine