Stabilization of the Transcription Factor Foxp3 by the Deubiquitinase USP7 Increases Treg-Cell-Suppressive Capacity

Abstract

SUMMARY Stable Foxp3 expression is required for the development of functional regulatory T (Treg) cells. Here, we demonstrate that the expression of the transcription factor Foxp3 can be regulated through the polyubiquitination of multiple lysine residues, resulting in proteasome-mediated degradation. Expression of the deubiquitinase (DUB) USP7 was found to be upregulated and active in Treg cells, being associated with Foxp3 in the nucleus. Ectopic expression of USP7 decreased Foxp3 polyubiquitination and increased Foxp3 expression. Conversely, either treatment with DUB inhibitor or USP7 knockdown decreased endogenous Foxp3 protein expression and decreased Treg-cell-mediated suppression in vitro. Furthermore, in a murine adoptive-transfer-induced colitis model, either inhibition of DUB activity or USP7 knockdown in Treg cells abrogated their ability to resolve inflammation in vivo. Our data reveal a molecular mechanism in which rapid temporal control of Foxp3 expression in Treg cells can be regulated by USP7, thereby modulating Treg cell numbers and function.

FOXP3+ regulatory T cells and their functional regulation

“…74 Subsequently, FOXP3 was also found to undergo ubiquitination and the that ubiquitination would lead to its degradation. 31,55 Since both ubiquitination and acetylation are restricted to lysine residues, acetylation may compete with poly-ubiquitination to stabilize FOXP3. 57 Two acetyltransferases, Tip60 and p300, have been reported as enzymes that are responsible for FOXP3 acetylation.…”

“…Further, adoptive transfer of USP7 knockdown or USP7 inhibitor-treated Treg cells have reduced function in resolving induced colitis in mice. 55 Phosphorylation is the most common studied post-translational modification of proteins. 79 It has been reported that phosphorylation at Ser418 in the C-terminal DNA binding domain of FOXP3 positively regulates its DNA binding activity and transcriptional regulation that affects Treg cell suppressive function.…”

“…A PIM1-specific inhibitor could potentially be used to enhance the immunosuppressive activity of Treg cells through downregulating the phosphorylation of FOXP3-Ser422 during ex vivo preparation of Treg cells, 54 while PP1-specific inhibitor may work reversely and weaken the immunosuppressive activity of Treg cells; 60 STUB1-specific inhibitors, may stabilize Treg cells through preventing FOXP3 ubiquitination and degradation, whereas USP7-specific inhibitor treated Treg cells may lose their stability through promoting the process; 31,55 SIRT1/HDAC9 inhibitors would enhance the activity of Treg cells through promoting FOXP3 acetylation and facilitating its stability or activity upregulation, while P300/TIP60 inhibitors may abolish the process and promote FOXP3 degradation mediated by FOXP3 ubiquitination. 53,57,75,76 Along with the accumulation of our knowledge on the molecular mechanism of Treg immunosuppressive activity, we expect that in the next few years, increasingly safe and effective compounds, which could aid the ex vivo expansion of Treg cells by helping to maintain their stable function in vivo, will be identified and advance into clinical trials for the treatment of autoimmune diseases and other inflammatory diseases.…”

Effect of chromium disilicide and titanium nitride nanoparticles on the expression of NAMPT, E2F8, FAS, TBX3, IL13RA2, and UPS7 genes in mouse liver

“…Moreover, low-dose cadmium has growth-promoting effects on NPrEC cells and induces transient overexpression of genes with oncogenic and immunomodulation functions, including TNF and Il13ra2 [17]. Ubiquitin specific peptidase 7 (USP7), also known as herpes virus-associated ubiquitin-specific protease (HAUSP), is hydrolase that deubiquitinates target proteins such as FOXO4, p53/TP53, MDM2, PTEN, PPARG, and other and thus participate in control of cell growth repression and apoptosis [18][19][20]. There is data that early adipogenesis is regu lated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60 [21].…”

How regulatory T cells sense and adapt to inflammation

“…[3][4][5] On the other hand, the Foxp3 protein is regulated at the posttranslational level by acetylation, phosphorylation, and ubiquitination, which detemine its DNA binding, protein stability, and degradation under inflammation. [6][7][8][9][10] Understanding functional plasticity and stability could provide new insights in promoting Treg-based clinical therapies for autoimmune disease, organ transplantation, and cancer. 11 In this issue, we have assembled a series of up-to-date reviews on the functional plasticity of Tregs to address and discuss how Tregs may sense the initiation and progression of inflammation in different physiological microenvironments.…”