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Journal of Virology, December 2006, p. 11911-11919, Vol. 80, No. 24
0022-538X/06/$08.00+0     doi:10.1128/JVI.01565-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role of Ran Binding Protein 5 in Nuclear Import and Assembly of the Influenza Virus RNA Polymerase Complex{triangledown}

Tao Deng,1,{dagger} Othmar G. Engelhardt,1,{dagger},{ddagger} Benjamin Thomas,2 Alexandre V. Akoulitchev,2 George G. Brownlee,1 and Ervin Fodor1*

Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom,1 Oxford Central Proteomics Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom2

Received 21 July 2006/ Accepted 21 September 2006

The influenza A virus RNA-dependent RNA polymerase is a heterotrimeric complex of polymerase basic protein 1 (PB1), PB2, and polymerase acidic protein (PA) subunits. It performs transcription and replication of the viral RNA genome in the nucleus of infected cells. We have identified a nuclear import factor, Ran binding protein 5 (RanBP5), also known as karyopherin ß3, importin ß3, or importin 5, as an interactor of the PB1 subunit. RanBP5 interacted with either PB1 alone or with a PB1-PA dimer but not with a PB1-PB2 dimer or the trimeric complex. The interaction between RanBP5 and PB1-PA was disrupted by RanGTP in vitro, allowing PB2 to bind to the PB1-PA dimer to form a functional trimeric RNA polymerase complex. We propose a model in which RanBP5 acts as an import factor for the newly synthesized polymerase by targeting the PB1-PA dimer to the nucleus. In agreement with this model, small interfering RNA (siRNA)-mediated knock-down of RanBP5 inhibited the nuclear accumulation of the PB1-PA dimer. Moreover, siRNA knock-down of RanBP5 resulted in the delayed accumulation of viral RNAs in infected cells, confirming that RanBP5 plays a biological role during the influenza virus life cycle.

* Corresponding author. Mailing address: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom. Phone: 44 1865 275580. Fax: 44 1865 275556. E-mail: ervin.fodor{at}path.ox.ac.uk.

{triangledown} Published ahead of print on 27 September 2006.

{dagger} These authors contributed equally to this study.

{ddagger} Present address: Division of Virology, National Institute for Biological Standards and Control, South Mimms, Potters Bar EN6 3QG, United Kingdom.

Journal of Virology, December 2006, p. 11911-11919, Vol. 80, No. 24
0022-538X/06/$08.00+0     doi:10.1128/JVI.01565-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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