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J. Biol. Chem., Vol. 280, Issue 50, 41568-41575, December 16, 2005

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Evidence for Direct Roles of Two Additional Factors, SECp43 and Soluble Liver Antigen, in the Selenoprotein Synthesis Machinery^*

Xue-Ming Xu, Heiko Mix, Bradley A. Carlson, Paula J. Grabowski¶, Vadim N. Gladyshev, Marla J. Berry||, and Dolph L. Hatfield1

From the Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, the Department of Biochemistry, University of Nebraska, Lincoln, Nebraska 68588, the ^¶Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, and the ^||Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii 96822

Selenocysteine (Sec) is inserted into selenoproteins co-translationally with the help of various cis- and trans-acting factors. The specific mechanisms of Sec biosynthesis and insertion into protein in eukaryotic cells, however, are not known. Two proteins, SECp43 and the soluble liver antigen (SLA), were previously reported to interact with tRNA^[Ser]Sec, but their functions remained elusive. Herein, we report that knockdown of SECp43 in NIH3T3 or TCMK-1 cells using RNA interference technology resulted in a reduction in the level of methylation at the 2'-hydroxylribosyl moiety in the wobble position (Um34) of Sec tRNA^[Ser]Sec, and consequently reduced glutathione peroxidase 1 expression. Double knockdown of SECp43 and SLA resulted in decreased selenoprotein expression. SECp43 formed a complex with Sec tRNA^[Ser]Sec and SLA, and the targeted removal of one of these proteins affected the binding of the other to Sec tRNA^[Ser]Sec. SECp43 was located primarily in the nucleus, whereas SLA was found in the cytoplasm. Co-transfection of both proteins resulted in the nuclear translocation of SLA suggesting that SECp43 may also promote shuttling of SLA and Sec tRNA^[Ser]Sec between different cellular compartments. Taken together, these data establish the role of SECp43 and SLA in selenoprotein biosynthesis through interaction with tRNA^[Ser]Sec in a multiprotein complex. The data also reveal a role of SECp43 in regulation of selenoprotein expression by affecting the synthesis of Um34 on tRNA^[Ser]Sec and the intracellular location of SLA.

Received for publication, June 20, 2005 , and in revised form, October 14, 2005.

^* This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and by Grant GM061603 from the National Institutes of Health (to V. N. G.). 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.

¹ To whom correspondence should be addressed: MBSS, LCP, CCR, Bldg. 37, Rm. 6032A, NCI, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-496-2797; Fax: 301-435-4957; E-mail: hatfield{at}dc37a.nci.nih.gov.

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