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J. Virol. doi:10.1128/JVI.02303-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Respiratory Syncytial Virus NS1 protein degrades STAT2 using the Elongin-Cullin E3 ligase

Molecular Immunology and; Molecular Virology, Infection and Immunity Group, Centre for Cancer Research and Cell Biology, Queens University Belfast, N. Ireland; Fusion Antibodies Ltd, PO box 374, Belfast, BT1 2WD, N. Ireland

^* To whom correspondence should be addressed. Email: u.power{at}qub.ac.uk. jim.johnston{at}qub.ac.uk.

	Abstract

Respiratory Syncytial Virus (RSV) infection causes bronchiolitis and pneumonia in infants. RSV has a linear single-stranded RNA genome encoding 11 proteins, two of which are non-structural (NS1 and NS2). RSV specifically downregulates STAT2 protein expression thus enabling the virus to evade the host type 1 interferon response. Degradation of STAT2 requires proteasomal activity and is dependent upon the expression of RSV 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 ElonginC and Cullin2 binding consensus sequences and can interact with ElonginC and Cullin2 in vitro and therefore has the potential to act as an E3 ligase. By knocking down expression of specific endogenous E3 ligase components using siRNA, 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.

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