Alternative Splicing Factor/Splicing Factor 2 Regulates the Expression of the ζ Subunit of the Human T Cell Receptor-associated CD3 Complex

T cells from patients with systemic lupus erythematosus express decreased levels of the T cell receptor-associated CD3 zeta chain, a feature directly linked to their aberrant function. The decrease in CD3 zeta protein expression is in part due to decreased levels of functional wild type isoform of the 3'-untranslated region (UTR) of CD3 zeta mRNAwith concomitant increased levels of an unstable alternatively spliced isoform. In order to identify factors involved in the post-transcriptional regulation of CD3 zeta, we performed mass spectrometric analysis of Jurkat T cell nuclear proteins pulled down by a CD3 zeta 3'-UTR oligonucleotide, which identified the splicing protein alternative splicing factor/splicing factor 2 (ASF/SF2). We show for the first time that ASF/SF2 binds specifically to the 3'-UTR of CD3 zeta and regulates expression of CD3 zeta protein by limiting the production of the alternatively spliced isoform. During activation of human T cells, an increase in the wild type CD3 zeta mRNAis associated with increased expression of ASF/SF2. Finally, we show a significant correlation between ASF/SF2 and CD3 zeta protein levels in T cells from systemic lupus erythematosus patients. Thus, our results identify ASF/SF2 as a novel factor in the regulation of alternative splicing of the 3'-UTR of CD3 zeta and protein expression in human T cells.