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Journal of Virology, July 2009, p. 6631-6640, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00367-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Molecular Determinants for Subcellular Localization of the Severe Acute Respiratory Syndrome Coronavirus Open Reading Frame 3b Protein {triangledown}

Eric C. Freundt,1,2 Li Yu,1 Elizabeth Park,1 Michael J. Lenardo,1 and Xiao-Ning Xu2*

Laboratory of Immunology, Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,1 Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom2

Received 18 February 2009/ Accepted 16 April 2009

Viruses such as hepatitis C and the severe acute respiratory syndrome coronavirus (SARS-CoV) encode proteins that are distributed between mitochondria and the nucleus, but little is known about the factors that control partitioning between these sites. SARS-CoV encodes a unique accessory gene called open reading frame (ORF) 3b that, like other unique accessory genes in SARS-CoV, likely contributes to viral pathogenicity. The ORF 3b protein is 154 amino acids and is predicted to express from the second ORF in subgenomic RNA3. In this report, we have characterized the molecular components that regulate intracellular localization of the ORF 3b protein. We demonstrate unique shuttling behavior of ORF 3b, whereby the protein initially accumulates in the nucleus and subsequently translocates to mitochondria. Following nuclear localization, ORF 3b traffics to the outer membrane of mitochondria via a predicted amphipathic {alpha}-helix. Additionally, ORF 3b contains a consensus nuclear export sequence, and we demonstrate that nuclear export and thus mitochondrial translocation are dependent on a leptomycin B-sensitive nuclear export mechanism. We further show that ORF 3b inhibits induction of type I interferon induced by retinoic acid-induced gene 1 and the mitochondrial antiviral signaling protein. Our observations provide insights into the cellular localization of ORF 3b that may enhance our understanding of the mechanisms by which ORF 3b contributes to SARS-CoV pathogenesis. The findings reported here reveal that for multilocalized proteins, consideration of the spatiotemporal distribution may be crucial for understanding viral protein behavior and function.

* Corresponding author. Mailing address: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom. Phone: 44 1865 222401. Fax: 44 1865 222628. E-mail: xiaoning.xu{at}imm.ox.ac.uk

{triangledown} Published ahead of print on 29 April 2009.

Journal of Virology, July 2009, p. 6631-6640, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00367-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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