SENP3 maintains the stability and function of regulatory T cells via BACH2 deSUMOylation

Xiaoyan Yu,Xuefeng Wu,Feixiang Wang,Yuzhou Chang,Yimin Lao,Hua Bing Li ,Lei Chen,Xinwei Guo,Jintao Wang ,Yan Zhou,Li Lu ,Xiao Lu Teng ,Zhiduo Liu,Jinke Cheng,Chuanxin Huang,Bing Su,Bin Li,Jing Yi,Jin Jen ,Siyu Deng,Qiang Zou

doi:10.1038/s41467-018-05676-6

Abstract

Regulatory T (Treg) cells are essential for maintaining immune homeostasis and tolerance, but the mechanisms regulating the stability and function of Treg cells have not been fully elucidated. Here we show SUMO-specific protease 3 (SENP3) is a pivotal regulator of Treg cells that functions by controlling the SUMOylation and nuclear localization of BACH2. Treg cell-specific deletion of Senp3 results in T cell activation, autoimmune symptoms and enhanced antitumor T cell responses. SENP3-mediated BACH2 deSUMOylation prevents the nuclear export of BACH2, thereby repressing the genes associated with CD4+ T effector cell differentiation and stabilizing Treg cell-specific gene signatures. Notably, SENP3 accumulation triggered by reactive oxygen species (ROS) is involved in Treg cell-mediated tumor immunosuppression. Our results not only establish the role of SENP3 in the maintenance of Treg cell stability and function via BACH2 deSUMOylation but also clarify the function of SENP3 in the regulation of ROS-induced immune tolerance.

Highlights

Regulatory T (Treg) cells are essential for maintaining immune homeostasis and tolerance, but the mechanisms regulating the stability and function of Treg cells have not been fully elucidated
We show that SENP3 regulates Treg cell stability and function by promoting BACH2 deSUMOylation, which in turn prevents the nuclear export of BACH2 to repress Teff cell-transcriptional programs and maintain Treg cell-specific gene signatures
To assess the function of SENP3 in immune cells, we first analyzed its expression at the protein level and found that SENP3 was highly expressed in T cells (Supplementary Fig. 1a)

Summary

Introduction

Regulatory T (Treg) cells are essential for maintaining immune homeostasis and tolerance, but the mechanisms regulating the stability and function of Treg cells have not been fully elucidated. We show SUMO-specific protease 3 (SENP3) is a pivotal regulator of Treg cells that functions by controlling the SUMOylation and nuclear localization of BACH2. Our results establish the role of SENP3 in the maintenance of Treg cell stability and function via BACH2 deSUMOylation and clarify the function of SENP3 in the regulation of ROS-induced immune tolerance. SUMOylation plays a functional role in the regulation of activities of specific transcription factors by mediating protein stability, nuclear transport, recruitment of chromatin remodeling machinery or transcriptional regulation[12,13,14]. The loss of SUMOconjugating enzyme UBC9 inhibits Treg cell expansion and function, leading to severe autoimmune diseases[17] It is still unknown whether SENP-mediated deSUMOylation regulates transcriptional programs in different types of immune cells, especially in Treg cells. It is of interest to determine whether SENP3 is a critical regulator of ROS-induced immune tolerance

Methods

Results

Conclusion