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Journal of Virology, November 2008, p. 10776-10791, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01180-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Differential Modulation of prM Cleavage, Extracellular Particle Distribution, and Virus Infectivity by Conserved Residues at Nonfurin Consensus Positions of the Dengue Virus pr-M Junction{triangledown}

Jiraphan Junjhon,1 Matthawee Lausumpao,1 Sunpetchuda Supasa,1 Sansanee Noisakran,2 Adisak Songjaeng,1 Prakaimuk Saraithong,1 Kridsada Chaichoun,1 Utaiwan Utaipat,3 Poonsook Keelapang,1 Amornrat Kanjanahaluethai,1 Chunya Puttikhunt,2 Watchara Kasinrerk,4,5 Prida Malasit,2,6 and Nopporn Sittisombut1,2*

Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand,1 Medical Biotechnology Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Bangkok, Thailand,2 Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand,3 Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand,4 Biomedical Technology Research Center, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Bangkok, Thailand,5 Medical Molecular Biology Unit, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand6

Received 6 June 2008/ Accepted 8 August 2008

In the generation of flavivirus particles, an internal cleavage of the envelope glycoprotein prM by furin is required for the acquisition of infectivity. Unlike cleavage of the prM of other flaviviruses, cleavage of dengue virus prM is incomplete in many cell lines; the partial cleavage reflects the influence of residues at furin nonconsensus positions of the pr-M junction, as flaviviruses share basic residues at positions P1, P2, and P4, recognized by furin. In this study, viruses harboring the alanine-scanning and other multiple-point mutations of the pr-M junction were generated, employing a dengue virus background that exhibited 60 to 70% prM cleavage and a preponderance of virion-sized extracellular particles. Analysis of prM and its cleavage products in viable mutants revealed a cleavage-suppressive effect at the conserved P3 Glu residue, as well as the cleavage-augmenting effects at the P5 Arg and P6 His residues, indicating an interplay between opposing modulatory influences mediated by these residues on the cleavage of the pr-M junction. Changes in the prM cleavage level were associated with altered proportions of extracellular virions and subviral particles; mutants with reduced cleavage were enriched with subviral particles and prM-containing virions, whereas the mutant with enhanced cleavage was deprived of these particles. Alterations of virus multiplication were detected in mutants with reduced prM cleavage and were correlated with their low specific infectivities. These findings define the functional roles of charged residues located adjacent to the furin consensus sequence in the cleavage of dengue virus prM and provide plausible mechanisms by which the reduction in the pr-M junction cleavability may affect virus replication.

* Corresponding author. Mailing address: Department of Microbiology, Faculty of Medicine, Chiang Mai University, 110 Intawaroros Street, Chiang Mai 50200, Thailand. Phone: 66-53-945334. Fax: 66-53-217144. E-mail: nsittiso{at}mail.med.cmu.ac.th

{triangledown} Published ahead of print on 20 August 2008.

Journal of Virology, November 2008, p. 10776-10791, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01180-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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