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Journal of Virology, April 2007, p. 3428-3436, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02303-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Respiratory Syncytial Virus NS1 Protein Degrades STAT2 by Using the Elongin-Cullin E3 Ligase{triangledown}

Joanne Elliott,1 Oonagh T. Lynch,1 Yvonne Suessmuth,1 Ping Qian,2 Caroline R. Boyd,1 James F. Burrows,1 Richard Buick,3 Nigel J. Stevenson,1 Olivier Touzelet,2 Massimo Gadina,1 Ultan F. Power,2* and James A. Johnston1*

Molecular Immunology,1 Molecular Virology, Infection and Immunity Group, Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast,2 Fusion Antibodies Ltd., P.O. Box 374, Belfast, BT1 2WD, Northern Ireland3

Received 20 October 2006/ Accepted 29 December 2006

Respiratory syncytial virus (RSV) infection causes bronchiolitis and pneumonia in infants. RSV has a linear single-stranded RNA genome encoding 11 proteins, 2 of which are nonstructural (NS1 and NS2). RSV specifically downregulates STAT2 protein expression, thus enabling the virus to evade the host type I interferon response. Degradation of STAT2 requires proteasomal activity and is dependent on the expression of RSV NS1 and NS2 (NS1/2). Here we investigate whether RSV NS proteins can assemble ubiquitin ligase (E3) enzymes to target STAT2 to the proteasome. We demonstrate that NS1 contains elongin C and cullin 2 binding consensus sequences and can interact with elongin C and cullin 2 in vitro; therefore, NS1 has the potential to act as an E3 ligase. By knocking down expression of specific endogenous E3 ligase components using small interfering RNA, NS1/2, or RSV-induced STAT2, degradation is prevented. These results indicate that E3 ligase activity is crucial for the ability of RSV to degrade STAT2. These data may provide the basis for therapeutic intervention against RSV and/or logically designed live attenuated RSV vaccines.

* Corresponding author. Mailing address for James A. Johnston: CCRCB, QUB, 2nd Floor, Whitla Medical Building, 97 Lisburn Rd., Belfast, BT9 7BL, Northern Ireland. Phone: 44-2890272260. Fax: 44-2890325839. E-mail: jim.johnston{at}qub.ac.uk. Mailing address for Ultan F. Power: CCRCB, QUB, School of Medicine, Grosvenor Road, Belfast, BT12 6BN, Northern Ireland. Phone: 44-2890635006. Fax: 44-2890635024. E-mail: u.power{at}qub.ac.uk.

{triangledown} Published ahead of print on 24 January 2007.

Journal of Virology, April 2007, p. 3428-3436, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02303-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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