The RNA-stabilizing protein HuR regulates the expression of zeta 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 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.
Moulton
Vaishali R
VR
Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Kyttaris
Vasileios C
VC
Juang
Yuang-Taung
YT
Chowdhury
Bhabadeb
B
Tsokos
George C
GC
D020413:3' Untranslated Regions / Q000235:genetics; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism*; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D011485:Protein Binding; D020871:RNA Stability; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements
D020413:3' Untranslated Regions; D000954:Antigens, Surface; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D016601:RNA-Binding Proteins