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Molecular and Cellular Biology, July 2006, p. 4895-4910, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.02284-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Redox State of SECIS Binding Protein 2 Controls Its Localization and Selenocysteine Incorporation Function

Laura V. Papp,1,2 Jun Lu,3 Frank Striebel,3 Derek Kennedy,2 Arne Holmgren,3 and Kum Kum Khanna1*

Queensland Institute of Medical Research, 300 Herston Rd., 4029 Herston, Queensland, Australia,1 School of Biomolecular and Biomedical Science, Eskitis Institute for Cell and Molecular Therapies, Griffith University, 4111 Nathan, Queensland, Australia,2 Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE-171 77 Stockholm, Sweden3

Received 29 November 2005/ Returned for modification 21 December 2005/ Accepted 15 April 2006

Selenoproteins are central controllers of cellular redox homeostasis. Incorporation of selenocysteine (Sec) into selenoproteins employs a unique mechanism to decode the UGA stop codon. The process requires the Sec insertion sequence (SECIS) element, tRNASec, and protein factors including the SECIS binding protein 2 (SBP2). Here, we report the characterization of motifs within SBP2 that regulate its subcellular localization and function. We show that SBP2 shuttles between the nucleus and the cytoplasm via intrinsic, functional nuclear localization signal and nuclear export signal motifs and that its nuclear export is dependent on the CRM1 pathway. Oxidative stress induces nuclear accumulation of SBP2 via oxidation of cysteine residues within a redox-sensitive cysteine-rich domain. These modifications are efficiently reversed in vitro by human thioredoxin and glutaredoxin, suggesting that these antioxidant systems might regulate redox status of SBP2 in vivo. Depletion of SBP2 in cell lines using small interfering RNA results in a decrease in Sec incorporation, providing direct evidence for its requirement for selenoprotein synthesis. Furthermore, Sec incorporation is reduced substantially after treatment of cells with agents that cause oxidative stress, suggesting that nuclear sequestration of SBP2 under such conditions may represent a mechanism to regulate the expression of selenoproteins.

* Corresponding author. Mailing address: Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland 4029, Australia. Phone: 61 7 33620338. Fax: 61 7 33620105. E-mail: kumkumK{at}qimr.edu.au.

Molecular and Cellular Biology, July 2006, p. 4895-4910, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.02284-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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