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 CD3zeta chain in SLE are not clear. SLE T cells express abnormally increased levels of an alternatively spliced isoform of CD3zeta 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 CD3zeta transcript are critical for the mRNA stability and protein expression of CD3zeta. In this study we show for the first time that the mRNA-stabilizing protein HuR binds to these two ARE bearing regions of CD3zeta 3'-UTR. Knockdown of HuR resulted in decreased expression of the CD3zeta chain, whereas overexpression led to the increase of CD3zeta chain levels. Additionally, overexpression of HuR in human T cells resulted in increased mRNA stability of CD3zeta. Our results identify the 3'-UTR of CD3zeta as a novel target for the mRNA-stabilizing protein HuR. Thus, the absence of two critical AREs in the alternatively spliced CD3zeta 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 CD3zeta in SLE.
Highlights
T cell dysfunction is crucial to the pathogenesis of systemic lupus erythematosus (SLE); the molecular mechanisms involved in the deficient expression of the T cell receptor-associated CD3 chain in SLE are not clear
Chowdhury et al [12] showed that a mutation of the AUUUA to GGGUA in either ARE2 or ARE3 of CD3 3Ј-untranslated region (UTR) led to a significant reduction in the mRNA stability and protein expression of CD3, indicating that the ARE2 and ARE3 regions positively regulate the integrity of CD3 mRNA
First we show that several putative proteins bind to the ARE2 bearing region of the 3Ј-UTR of CD3
Summary
T cell dysfunction is crucial to the pathogenesis of systemic lupus erythematosus (SLE); the molecular mechanisms involved in the deficient expression of the T cell receptor-associated CD3 chain in SLE are not clear. SLE T cells express abnormally increased levels of an alternatively spliced isoform of CD3 that lacks a 562-bp region in its 3-untranslated region (UTR). In this study we show for the first time that the mRNA-stabilizing protein HuR binds to these two ARE bearing regions of CD3 3-UTR.
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