Serine Arginine-Rich Splicing Factor 1 (SRSF1) Contributes to the Transcriptional Activation of CD3ζ in Human T Cells

被引:14
|
作者
Moulton, Vaishali R. [1 ]
Gillooly, Andrew R. [1 ]
Perl, Marcel A. [1 ]
Markopoulou, Anastasia [1 ]
Tsokos, George C. [1 ]
机构
[1] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Rheumatol,Dept Med, Boston, MA 02215 USA
来源
PLOS ONE | 2015年 / 10卷 / 07期
基金
美国国家卫生研究院;
关键词
SYSTEMIC-LUPUS-ERYTHEMATOSUS; RECEPTOR ZETA-CHAIN; TCR-ZETA; SR PROTEINS; 3'-UNTRANSLATED REGION; MESSENGER-RNA; CD3; COMPLEX; EXPRESSION; PROMOTER; PHOSPHORYLATION;
D O I
10.1371/journal.pone.0131073
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
T lymphocytes from many patients with systemic lupus erythematosus (SLE) express decreased levels of the T cell receptor (TCR)-associated CD3 zeta (zeta) signaling chain, a feature directly linked to their abnormal phenotype and function. Reduced mRNA expression partly due to defective alternative splicing, contributes to the reduced expression of CD3 zeta chain. We previously identified by oligonucleotide pulldown and mass spectrometry approaches, the serine arginine-rich splicing factor 1 (SRSF1) binding to the 3'untranslated region (UTR) of CD3 zeta mRNA. We showed that SRSF1 regulates alternative splicing of the 3'UTR of CD3 zeta to promote expression of the normal full length 3'UTR over an unstable splice variant in human T cells. In this study we show that SRSF1 regulates transcriptional activation of CD3 zeta. Specifically, overexpression and silencing of SRSF1 respectively increases and decreases CD3 zeta total mRNA and protein expression in Jurkat and primary T cells. Using promoter-luciferase assays, we show that SRSF1 enhances transcriptional activity of the CD3 zeta promoter in a dose dependent manner. Chromatin immunoprecipitation assays show that SRSF1 is recruited to the CD3 zeta promoter. These results indicate that SRSF1 contributes to transcriptional activation of CD3 zeta. Thus our study identifies a novel mechanism whereby SRSF1 regulates CD3 zeta expression in human T cells and may contribute to the T cell defect in SLE.
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页数:13
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