Abstract
Regulatory T (Treg) cells are indispensable for immune homeostasis due to their roles in peripheral tolerance. As the master transcription factor of Treg cells, Forkhead box P3 (Foxp3) strongly regulates Treg function and plasticity. Because of this, considerable research efforts have been directed at elucidating the mechanisms controlling Foxp3 and its co-regulators. Such work is not only advancing our understanding on Treg cell biology, but also uncovering novel targets for clinical manipulation in autoimmune diseases, organ transplantation, and tumor therapies. Recently, many studies have explored the post-translational regulation of Foxp3, which have shown that acetylation, phosphorylation, glycosylation, methylation, and ubiquitination are important for determining Foxp3 function and plasticity. Additionally, some of these targets have been implicated to have great therapeutic values. In this review, we will discuss emerging evidence of post-translational regulations on Foxp3 in Treg cells and their exciting therapeutic applications.
Highlights
Thanks to the precious gift inherited from jawed fish ancestors thought to have lived some 500 million years ago, our immune defenses are equipped with a powerful adaptive arm with the ability to mount responses to a near-infinite diversity of targets [1]
With increasing regulatory mechanisms of Foxp3 being brought to light, the potential of manipulating Foxp3 at the post-translational level has increased dramatically
We believe two aspects will be important for future drug discovery: first, an in vivo, highthroughput target screening assay for agents capable of disrupting the posttranslational means of supporting Foxp3 expression and function and the stronger suppressive potency of Treg cells, and second, a high-throughput and cost-efficient pre-clinical drug examination platform for Treg-based therapies
Summary
Thanks to the precious gift inherited from jawed fish ancestors thought to have lived some 500 million years ago, our immune defenses are equipped with a powerful adaptive arm with the ability to mount responses to a near-infinite diversity of targets [1]. Ubiquitin-dependent modification involves many unique E3 ligases for either polyubiquitination-dependent proteasome degradation or monoubiquitinated modification for signaling cascades [28] Due to these features, post-translational regulation provides new insights into protein functions and therapeutic targets [29]. Since the post-translational regulation of Foxp has become, of late, an expansive topic, in this review, we will focus on a selective number of modifications, including phosphorylation, dephosphorylation, acetylation, deacetylation, methylation, glycosylation, ubiquitination, deubiquitination, and others. Among these modifications, we will put additional emphasis on ubiquitination and deubiquitination, and discuss some recent therapeutic applications of Treg cells to build a connection between basic research and clinical transformation
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