Abstract
Abstract T cells in patients with systemic lupus erythematosus (SLE) fail to control the aberrant autoimmune response and also infiltrate target organs. SLE T cells express low levels of the T cell receptor (TCR) CD3ζ chain, the main intracellular signal transducer upon antigen encounter. This deficiency is partially due to altered splicing of the CD3ζ mRNA. SLE T cells express a short alternatively spliced (AS) isoform of CD3ζ which is missing 562 nucleotides within its 3` untranslated region (UTR). This transcript is unstable and leads to reduced CD3ζ protein expression. We hypothesized that proteins binding to the splice-deleted region of the 3`UTR of CD3ζ play a role in regulating post transcriptional processing. Using an RNA oligonucleotide pulldown assay and mass spectrometry, we identified the serine/arginine-rich (SR) protein alternative splicing factor/ splicing factor 2 (ASF/SF2) as a putative protein binding to the CD3ζ 3`UTR. Specific knockdown of ASF/SF2 in Jurkat T cells led to a significant reduction in CD3ζ protein expression. Blocking of ASF/SF2 in human T cells with di-erythro-C6-ceramide enhanced the alternative splicing of CD3ζ, while overexpression of ASF/SF2 repressed this splicing. ASF/SF2 did not alter the RNA stability of CD3ζ. These data reveal a novel factor in the regulation of the post transcriptional processing of CD3ζ that may lead to altered CD3ζ chain expression in SLE.
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