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J. Biol. Chem., Vol. 280, Issue 19, 18959-18966, May 13, 2005

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Decreased Stability and Translation of T Cell Receptor mRNA with an Alternatively Spliced 3'-Untranslated Region Contribute to Chain Down-regulation in Patients with Systemic Lupus Erythematosus^*

Bhabadeb Chowdhury, Christos G. Tsokos, Sandeep Krishnan, James Robertson, Carolyn U. Fisher, Rahul G. Warke, Vishal G. Warke, Madhusoodana P. Nambiar, and George C. Tsokos¶||

From the Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910-7500 and the ^¶Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814

The molecular mechanisms involved in the aberrant expression of T cell receptor (TCR) chain of patients with systemic lupus erythematosus are not known. Previously we demonstrated that although normal T cells express high levels of TCR mRNA with wild-type (WT) 3' untranslated region (3' UTR), systemic lupus erythematosus T cells display significantly high levels of TCR mRNA with the alternatively spliced (AS) 3' UTR form, which is derived by splice deletion of nucleotides 672–1233 of the TCR transcript. Here we report that the stability of TCR mRNA with an AS 3' UTR is low compared with TCR mRNA with WT 3' UTR. AS 3' UTR, but not WT 3' UTR, conferred similar instability to the luciferase gene. Immunoblotting of cell lysates derived from transfected COS-7 cells demonstrated that TCR with AS 3' UTR produced low amounts of 16-kDa protein. In vitro transcription and translation also produced low amounts of protein from TCR with AS 3' UTR. Taken together our findings suggest that nucleotides 672–1233 bp of TCR 3' UTR play a critical role in its stability and also have elements required for the translational regulation of TCR chain expression in human T cells.

Received for publication, January 28, 2005 , and in revised form, February 24, 2005.

^* This work was supported by National Institutes of Health Grant RO1 AI42269. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both individuals contributed equally to this work.

^|| To whom correspondence should be addressed: WRAIR, Bldg. 503, Rm. 1A32, 503 Robert Grant Ave., Silver Spring, MD 20910. Tel.: 301-319-9911; Fax: 301-309-9133; E-mail: gtsokos{at}usuhs.mil.

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