Identification of the E3 Deubiquitinase Ubiquitin-specific Peptidase 21 (USP21) as a Positive Regulator of the Transcription Factor GATA3

• Published in: The Journal of biological chemistry 2013-03, Vol.288 (13), p.9373-9382
• Main Authors: Zhang, Jing, Chen, Chen, Hou, Xiaoxia, Gao, Yayi, Lin, Fang, Yang, Jing, Gao, Zhimei, Pan, Lina, Tao, Lianqin, Wen, Chijun, Yao, Zhengju, Tsun, Andy, Shi, Guochao, Li, Bin
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Asthma - metabolism; Cell Line, Tumor; Deubiquitinase; Deubiquitination; Forkhead Transcription Factors - biosynthesis; FOXP3; GATA3; GATA3 Transcription Factor - metabolism; Gene Expression Regulation; HEK293 Cells; Humans; Immunology; Immunosuppression; Lymphocyte Activation; Middle Aged; Promoter Regions, Genetic; Protein Processing, Post-Translational; Regulatory T Cells; T Cell Biology; T-Lymphocytes - metabolism; Transcription Repressor; Ubiquitin Thiolesterase - metabolism; Ubiquitin-dependent Protease; USP21
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.374744

The expression of the transcription factor GATA3 in FOXP3+ regulatory T (Treg) cells is crucial for their physiological function in limiting inflammatory responses. Although other studies have shown how T cell receptor (TcR) signals induce the up-regulation of GATA3 expression in Treg cells, the underlying mechanism that maintains GATA3 expression in Treg cells remains unclear. Here, we show how USP21 interacts with and stabilizes GATA3 by mediating its deubiquitination. In a T cell line model, we found that TcR stimulation promoted USP21 expression, which was further up-regulated in the presence of FOXP3. The USP21 mutant C221A reduced its capacity to stabilize GATA3 expression, and its knockdown led to the down-regulation of GATA3 protein expression in Treg cells. Furthermore, we found that FOXP3 could directly bind to the USP21 gene promoter and activated its transcription upon TcR stimulation. Finally, USP21, GATA3, and FOXP3 were found up-regulated in Treg cells that were isolated from asthmatic subjects. In summary, we have identified a USP21-mediated pathway that promotes GATA3 stabilization and expression at the post-translational level. We propose that this pathway forms an important signaling loop that stabilizes the expression of GATA3 in Treg cells. Background: GATA3 is regulated both transcriptionally and post-translationally. GATA3 is important for the function of FOXP3+ Treg cells. Results: USP21 prevents the ubiquitination and degradation of GATA3. Conclusion: USP21 is a positive regulator of GATA3 expression. Significance: The identification of a molecular pathway where USP21 positively controls GATA3 expression at the post-translational level reveals USP21 as a potential drug target to manipulate the function of T cells.