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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.

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