Stability and Translation of TCR ζ mRNA Are Regulated by the Adenosine-Uridine-Rich Elements in Splice-Deleted 3′ Untranslated Region of ζ-Chain

Systemic lupus erythematosus (SLE) T cells display reduced expression of TCR ζ protein. Recently, we reported that in SLE T cells, the residual TCR ζ protein is predominantly derived from an alternatively spliced form that undergoes splice deletion of 562 nt (from 672 to 1233 bases) within the 3′ untranslated region (UTR) of TCR ζ mRNA. The stability and translation of the alternatively spliced form of TCR ζ mRNA are low compared with that of the wild-type TCR ζ mRNA. We report that two adenosine-uridine-rich sequence elements (AREs), defined by the splice-deleted 3′ UTR region, but not an ARE located upstream are responsible for securing TCR ζ mRNA stability and translation. The stabilizing effect of the splice-deleted region-defined AREs extended to the luciferase mRNA and was not cell type-specific. The findings demonstrate distinct sequences within the splice-deleted region 672 to 1233 of the 3′ UTR, which regulate the transcription, mRNA stability, and translation of TCR ζ mRNA. The absence of these sequences represents a molecular mechanism that contributes to altered TCR ζ-chain expression in lupus.