Abstract
T lymphocytes from many patients with systemic lupus erythematosus (SLE) express decreased levels of the T cell receptor (TCR)-associated CD3 zeta (ζ) 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 CD3ζ 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 CD3ζ mRNA. We showed that SRSF1 regulates alternative splicing of the 3’UTR of CD3ζ 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 CD3ζ. Specifically, overexpression and silencing of SRSF1 respectively increases and decreases CD3ζ total mRNA and protein expression in Jurkat and primary T cells. Using promoter-luciferase assays, we show that SRSF1 enhances transcriptional activity of the CD3ζ promoter in a dose dependent manner. Chromatin immunoprecipitation assays show that SRSF1 is recruited to the CD3ζ promoter. These results indicate that SRSF1 contributes to transcriptional activation of CD3ζ. Thus our study identifies a novel mechanism whereby SRSF1 regulates CD3ζ expression in human T cells and may contribute to the T cell defect in SLE.
Highlights
Systemic lupus erythematosus (SLE) is a chronic debilitating disease, which afflicts mainly women in the childbearing years
We identified the serine arginine-rich splicing factor 1 (SRSF1) in that analysis and confirmed SRSF1 binding to the 3`untranslated region (UTR) of CD3z mRNA
In this study we present several novel findings—we show that the splicing factor SRSF1 positively regulates total protein and mRNA expression of CD3z, second we show that SRSF1 regulates transcriptional activity of the CD3z promoter and that SRSF1 is recruited to the CD3z promoter
Summary
Systemic lupus erythematosus (SLE) is a chronic debilitating disease, which afflicts mainly women in the childbearing years. Dysfunctional cellular and antibody responses contribute to the etio-pathogenesis of this autoimmune disease. Autoantibodies and immune complexes deposit in target tissues such as kidneys and lead to organ failure. T lymphocytes play an important role in SLE pathophysiology– do they provide cognate help to autoreactive B cells, and contribute to cytokine imbalance and infiltrate target organs leading to tissue damage [1, 2].
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