The RNA-stabilizing protein HuR regulates the expression of ζ chain of the human T cell receptor-associated CD3 complex

T cell dysfunction is crucial to the pathogenesis of systemic lupus erythematosus (SLE); however, the molecular mechanisms involved in the deficient expression of the T cell receptor-associated CD3 zeta chain in SLE are not clear. SLE T cells express abnormally increased levels of an alternatively spliced isoform of CD3 zeta that lacks a 562-bp region in its 3'-untranslated region (UTR). We showed previously that two adenosine/uridine-rich elements (ARE) in this splice-deleted region of CD3 zeta transcript are critical for the mRNA stability and protein expression of CD3 zeta. In this study we show for the first time that the mRNA-stabilizing protein HuR binds to these two ARE bearing regions of CD3 zeta 3'-UTR. Knockdown of HuR resulted in decreased expression of the CD3 zeta chain, whereas overexpression led to the increase of CD3 zeta chain levels. Additionally, overexpression of HuR in human T cells resulted in increased mRNA stability of CD3 zeta. Our results identify the 3'-UTR of CD3 zeta as a novel target for the mRNA-stabilizing protein HuR. Thus, the absence of two critical AREs in the alternatively spliced CD3 zeta 3'-UTR found in SLE T cells may result in decreased HuR binding, representing a possible molecular mechanism contributing to the reduced stability and expression of CD3 zeta zeta in SLE.