title: Identification of the E3 deubiquitinase ubiquitin-specific peptidase 21 (USP21) as a positive regulator of the transcription factor GATA3.
abstract: 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.
authors: Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 411 Hefei Road, Shanghai 200025, China.
authors: Jing
authors: J
authors: Zhang
authors: Chen
authors: C
authors: Chen
authors: Xiaoxia
authors: X
authors: Hou
authors: Yayi
authors: Y
authors: Gao
authors: Fang
authors: F
authors: Lin
authors: Jing
authors: J
authors: Yang
authors: Zhimei
authors: Z
authors: Gao
authors: Lina
authors: L
authors: Pan
authors: Lianqin
authors: L
authors: Tao
authors: Chijun
authors: C
authors: Wen
authors: Zhengju
authors: Z
authors: Yao
authors: Andy
authors: A
authors: Tsun
authors: Guochao
authors: G
authors: Shi
authors: Bin
authors: B
authors: Li
mesh_terms: D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000378:metabolism; D045744:Cell Line, Tumor; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D050990:GATA3 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008213:Lymphocyte Activation; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D013601:T-Lymphocytes / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C408875:USP21 protein, human; D043222:Ubiquitin Thiolesterase
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