Stability and Translation of T Cell Receptor zeta Chain are regulated by the Splice Deleted 562‐bp 3′UTR in Systemic Lupus Erythematosus Patients

Abstract

The molecular mechanisms involved in the diminished expression of the TCRζ mRNA of patients with systemic lupus erythematosus (SLE) remains unknown. Previously we demonstrated that while normal T cells express high levels of TCRζ with wild-type (WT) 3′ UTR, SLE T cells display significantly high levels of ζ chain with an alternatively spliced (AS) 3′ UTR form which is derived by splice deletion of 672 to 1233 of TCRζ chain transcript. The 3′UTRs of eukaryotic mRNAs are known to play a crucial role in post-transcriptional regulation of gene expression, stability and rates of degradation. Selective expression of TCRζ with very short AS 3′ UTR in SLE suggests that it plays an important role in the down regulation of TCRζ expression in SLE T cells. Recently we have reported that stability of TCRζ mRNA with an AS is low compared to WT 3′ UTR in SLE. Therefore, we conducted studies to determine the stability of TCRζ mRNA with a splice deleted (SD) 3′ UTR in SLE T cells, and the transport and subsequent translation of TCRζ with WT or AS 3′ UTR or SD in normal and SLE T cells. In this communication we demonstrate that SD 3′ UTR confers stability to TCRζ and contributes to increased levels of TCRζ mRNA. In addition, we show that the TCRζ mRNA with SD 3′ UTR displayed high level of translation efficiency leading to the production of high amounts of protein. Taken together our findings confirm that splice deleted 562-bp of TCRζ plays a critical role in its stability and translational regulation in human T cells.