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Journal of Virology, June 2006, p. 5397-5404, Vol. 80, No. 11
0022-538X/06/$08.00+0     doi:10.1128/JVI.02397-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

A Short Isoform of Human Cytomegalovirus US3 Functions as a Dominant Negative Inhibitor of the Full-Length Form

Jinwook Shin,1 Boyoun Park,1 Sungwook Lee,1 Youngkyun Kim,1 Bonita J. Biegalke,3 Seongman Kang,2 and Kwangseog Ahn1*

Department of Biological Sciences, Center for Functional Cellulomics, Seoul National University, Seoul 151-747, Korea,1 College of Life Science and Biotechnology, Korea University, Seoul 136-704, Korea,2 Department of Biomedical Sciences, 228 Irvine Hall, Ohio University College of Osteopathic Medicine, Athens, Ohio 457013

Received 15 November 2005/ Accepted 10 March 2006

Human cytomegalovirus encodes four unique short (US) region proteins, each of which is independently sufficient for causing the down-regulation of major histocompatibility complex (MHC) class I molecules on the cell surface. This down-regulation enables infected cells to evade recognition by cytotoxic T lymphocytes (CTLs) but makes them vulnerable to lysis by natural killer (NK) cells, which lyse those cells that lack MHC class I molecules. The 22-kDa US3 glycoprotein is able to down-regulate the surface expression of MHC class I molecules by dual mechanisms: direct endoplasmic reticulum retention by physical association and/or tapasin inhibition. The alternative splicing of the US3 gene generates two additional products, including 17-kDa and 3.5-kDa truncated isoforms; however, the functional significance of these isoforms during viral infection is unknown. Here, we describe a novel mode of self-regulation of US3 function that uses the endogenously produced truncated isoform. The truncated isoform itself neither binds to MHC class I molecules nor prevents the full-length US3 from interacting with MHC class I molecules. Instead, the truncated isoform associates with tapasin and competes with full-length US3 for binding to tapasin; thus, it suppresses the action of US3 that causes the disruption of the function of tapasin. Our results indicate that the truncated isoform of the US3 locus acts as a dominant negative regulator of full-length US3 activity. These data reflect the manner in which the virus has developed temporal survival strategies during viral infection against immune surveillance involving both CTLs and NK cells.

* Corresponding author. Mailing address: Department of Biological Sciences, Seoul National University, San 56-1, Sillim-dong, Gwanak-Gu, Seoul 151-747, Korea. Phone: 82-2-880-9233. Fax: 82-2-872-1993. E-mail: ksahn{at}snu.ac.kr.

Journal of Virology, June 2006, p. 5397-5404, Vol. 80, No. 11
0022-538X/06/$08.00+0     doi:10.1128/JVI.02397-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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