The RNA-stabilizing protein HuR regulates the expression of zeta chain of the human T cell receptor-associated CD3 complex. 2008

Vaishali R Moulton, and Vasileios C Kyttaris, and Yuang-Taung Juang, and Bhabadeb Chowdhury, and George C Tsokos
Department of Medicine, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.

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.

UI MeSH Term Description Entries
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000067780 ELAV-Like Protein 1 An RRM protein that binds to the 3'-UTR region of mRNAs and increases their stability. In EMBRYONIC STEM CELLS, it binds to poly-U elements and AU-rich elements (AREs) in the 3'-UTR of target mRNAs and preferentially binds mRNAs that are not methylated by N6-methyladenosine (m6A), to stabilize them and promote differentiation. ELAVL1 protein,HuR Antigen,HuR Paraneoplastic Encephalomyelitis Antigen,HuR Protein,Antigen, HuR,ELAV Like Protein 1,Protein, HuR,protein, ELAVL1
D000954 Antigens, Surface Antigens on surfaces of cells, including infectious or foreign cells or viruses. They are usually protein-containing groups on cell membranes or walls and may be isolated. Cell Surface Antigens,Surface Antigens,Surface Markers, Immunological,Cell Surface Antigen,Immunologic Surface Markers,Markers, Immunological Surface,Surface Antigen,Surface Markers, Immunologic,Antigen, Cell Surface,Antigen, Surface,Antigens, Cell Surface,Immunological Surface Markers,Markers, Immunologic Surface,Surface Antigen, Cell,Surface Antigens, Cell
D016601 RNA-Binding Proteins Proteins that bind to RNA molecules. Included here are RIBONUCLEOPROTEINS and other proteins whose function is to bind specifically to RNA. Double-Stranded RNA-Binding Protein,Double-Stranded RNA-Binding Proteins,ds RNA-Binding Protein,RNA-Binding Protein,ds RNA-Binding Proteins,Double Stranded RNA Binding Protein,Double Stranded RNA Binding Proteins,Protein, Double-Stranded RNA-Binding,Protein, ds RNA-Binding,RNA Binding Protein,RNA Binding Proteins,RNA-Binding Protein, Double-Stranded,RNA-Binding Protein, ds,RNA-Binding Proteins, Double-Stranded,ds RNA Binding Protein
D017252 CD3 Complex Complex of at least five membrane-bound polypeptides in mature T-lymphocytes that are non-covalently associated with one another and with the T-cell receptor (RECEPTORS, ANTIGEN, T-CELL). The CD3 complex includes the gamma, delta, epsilon, zeta, and eta chains (subunits). When antigen binds to the T-cell receptor, the CD3 complex transduces the activating signals to the cytoplasm of the T-cell. The CD3 gamma and delta chains (subunits) are separate from and not related to the gamma/delta chains of the T-cell receptor (RECEPTORS, ANTIGEN, T-CELL, GAMMA-DELTA). Antigens, CD3,CD3 Antigens,T3 Antigens,CD3 Antigen,T3 Antigen,T3 Complex,Antigen, CD3,Antigen, T3,Antigens, T3
D051959 ELAV Proteins A family of RRM PROTEINS that are homologues of ELAV protein, Drosophila. They were initially identified in humans as the targets of autoantibodies in patients with PARANEOPLASTIC ENCEPHALOMYELITIS. They regulate GENE EXPRESSION at the post-transcriptional level. Hu Paraneoplastic Encephalomyelitis Antigens,ELAV Protein,Embryonic Lethal, Abnormal Vision-Like Proteins,Hu Antigens,Antigens, Hu,Embryonic Lethal, Abnormal Vision Like Proteins,Protein, ELAV,Proteins, ELAV
D019169 Jurkat Cells A CELL LINE derived from human T-CELL LEUKEMIA and used to determine the mechanism of differential susceptibility to anti-cancer drugs and radiation. Cell, Jurkat,Cells, Jurkat,Jurkat Cell

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