PIM1 Kinase Phosphorylates the Human Transcription Factor FOXP3 at Serine 422 to Negatively Regulate Its Activity under Inflammation

Abstract

Background: FOXP3 is a key transcription factor for the development and function of Tregs. Results: PIM1-mediated phosphorylation of FOXP3 at serine 422 decreased its DNA binding activity. Conclusion: PIM1 negatively regulates FOXP3-mediated transcriptional regulation and the suppressive activity of Tregs. Significance: PIM1 is a newly identified negative regulator of the immunosuppressive activity of Tregs.

Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1

“…The role of Dbc1 may relate to Treg cells' stability and function. Dbc1 does not affect the development of nTreg cells, because the frequency and total number of thymic (24)(25)(26). The effect of the proinflammatory cytokine TNF-α on Treg cells remains controversial (28,29,(40)(41)(42).…”

“…Inflammation is beneficial for pathogen clearance and protection against infection; therefore restricting the activity of FOXP3 + Treg cells may be necessary to allow effective immune responses to occur during inflammation (2,(22)(23)(24)(25)(26). However, the molecular basis by which FOXP3 protein stability and Tregcell function are regulated during inflammation remains unclear.…”

“…FOXP3 has been shown to interact with the acetyltransferase Tat-interaction protein 60 kDa (TIP60) to promote FOXP3 acetylation, which is required for Treg cells' suppressive function (19). P300 also regulates (11); therefore, many questions remain regarding the differential modulation of this complex and its effect on Treg-cell differentiation and function.Inflammation is beneficial for pathogen clearance and protection against infection; therefore restricting the activity of FOXP3 + Treg cells may be necessary to allow effective immune responses to occur during inflammation (2,(22)(23)(24)(25)(26). However, the molecular basis by which FOXP3 protein stability and Tregcell function are regulated during inflammation remains unclear.…”

FOXP3+ regulatory T cells and their functional regulation

“…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.…”

Regulatory T cells turn pathogenic

“…In addition, the CDK2-mediated Foxp3 degradation and PIM1-mediated down-regulation of DNA binding activity of human FOXP3 are potentially involved in Treg cell instability. 48,49 With the loss of Foxp3 expression, Treg cells usually lose their suppressive function and obtain partial phenotypes and functions of effector Th cells, such as the production of IFN-c and IL-17. Given the crucial roles of Treg cells in immune balance, the instability of Treg cells, especially in local tissues, such as pancreas islets, disturbs the immune balance and unleashes a local pathogenic T-cell response.…”