Dynamic Interactions between TIP60 and p300 Regulate FOXP3 Function through a Structural Switch Defined by a Single Lysine on TIP60

Abstract

SUMMARY 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 post-translational level, in part by two histone acetyltransferases (HAT), 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.

The TIP60 Complex Is a Conserved Coactivator of HIF1A

“…Since histone H4 acetylation is affected by TIP60 knockdown at all genes analyzed, TIP60 effects could be driven by other acetylation targets in the transcriptional apparatus. In fact, several non-histone TIP60 targets, including transcription factors, have been identified (Patel et al, 2004; Sun et al, 2005; Tang et al, 2006; Tang et al, 2008; Xiao et al, 2014). …”

Pim-2 Kinase Influences Regulatory T Cell Function and Stability by Mediating Foxp3 Protein N-terminal Phosphorylation

“…Furthermore, the observation of the y4 ion eliminated the Thr-38 possibility, and the observation of y9 ion further confirmed the phosphorylation at the Ser-33 site. The same approach of using key MS2 spectrum ions was conducted for the phosphorylation site assignments for panels B and C. addition, we have observed that Tip60 and p300 modify distinct residues of the Foxp3 protein (32,33). Dephosphorylation of Ser-418 by PP1 at the C-terminal domain of FOXP3 may negatively regulate Treg cell function (17).…”

Transcriptional and Epigenetic Control of Regulatory T Cell Development

“…For example, human FOXP3 protein is capable of interacting with the coactivators p300 and TIP60 and such interaction promotes the transcriptional activity of FOXP3, while Treg cell-specific deletion of p300 and TIP60 results in loss of Treg function. 36 In contrast, Foxp3 recruits Eos and the corepressor CtBP1 to repress the expression of genes such as Il2. Since IL-2 repression is critical for Treg cell-mediated immune regulation, silencing Eos in Treg cells abrogates their suppressive function.…”

“…Some of the proteins currently reported to be capable of interacting with Foxp3 are NFκB, 32 NFAT, 22 Runx1, 28 Eos, CtBP1, 33 CBFb, Gata3, Ash2l, Bcl11b, Ikzf3, Foxp1, Smarcc1, Smarce1, Smarca4, Smarca5, Chd4, Hdac2, Rcor1, Lsd1, 34 HIF-1α, IRF-4, 35 p300, TIP60, 36 and Ezh2. 26 Though Foxp3 is likely to exist in a large protein complex, not all these cofactors are always found in the same complex.…”