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

Abstract

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 CD3ζ chain in SLE are not clear. SLE T cells express abnormally increased levels of an alternatively spliced isoform of CD3ζ 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 CD3ζ transcript are critical for the mRNA stability and protein expression of CD3ζ. In this study we show for the first time that the mRNA-stabilizing protein HuR binds to these two ARE bearing regions of CD3ζ 3′-UTR. Knockdown of HuR resulted in decreased expression of the CD3ζ chain, whereas overexpression led to the increase of CD3ζ chain levels. Additionally, overexpression of HuR in human T cells resulted in increased mRNA stability of CD3ζ. Our results identify the 3′-UTR of CD3ζ as a novel target for the mRNA-stabilizing protein HuR. Thus, the absence of two critical AREs in the alternatively spliced CD3ζ 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 CD3ζ in SLE.