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Journal of Virology, January 2003, p. 433-442, Vol. 77, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.1.433-442.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Regulation of Minute Virus of Mice NS1 Replicative Functions by Atypical PKC{lambda} In Vivo{dagger}

Jürg P. F. Nüesch,1,2* Sylvie Lachmann,1,2 Romuald Corbau,1,2 and Jean Rommelaere1,2

Program of Applied Tumor Virology, Abteilung F0100,1 Institut National de la Santé et de la Recherche Médicale U375, Deutsches Krebsforschungszentrum, Heidelberg, Germany2

Received 19 June 2002/ Accepted 27 September 2002

Minute virus of mice NS1 protein is a multifunctional phosphoprotein endowed with a variety of enzymatic and regulatory activities necessary for progeny virus particle production. To regulate all of its different functions in the course of a viral infection, NS1 has been proposed to be modulated by posttranslational modifications, in particular, phosphorylation. Indeed, it was shown that the NS1 phosphorylation pattern is altered during the infectious cycle and that the biochemical profile of the protein is dependent on the phosphorylation state of the polypeptide. Moreover, in vitro approaches have identified members of the protein kinase C (PKC) family, in particular, atypical PKC, as regulators of viral DNA replication through the phosphorylation of NS1 residues T435 and S473, thereby activating the protein for DNA unwinding activities. In order to substantiate these findings in vivo, we produced NS1 in the presence of a dominant-negative PKC{lambda} mutant and characterized the purified protein in vitro. The NS1 protein produced under these conditions was found to be only partially phosphorylated and as a consequence to be deficient for viral DNA replication. However, it could be rescued for this viral function by treatment with recombinant activated PKC{lambda}. Our data clearly demonstrate that NS1 is a target for PKC{lambda} phosphorylation in vivo and that this modification is essential for the helicase activity of the viral polypeptide. In addition, the phosphorylation of NS1 at residues T435 and S473 appeared to occur mainly in the nucleus, providing further evidence for the involvement of PKC{lambda} which, unlike PKC{zeta}, accumulates in the nuclear compartment of infected cells.

* Corresponding author. Mailing address: Program of Applied Tumor Virology, Abteilung F0100, and INSERM U375, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, D-69120 Heidelberg, Germany. Phone: (49) 6221 424969. Fax: (49) 6221 424962. E-mail: jpf.nuesch{at}dkfz-heidelberg.de.

{dagger} This article is dedicated to Harald zur Hausen on the occasion of his retirement as head of the Deutsches Krebsforschungszentrum, with gratitude and appreciation for 20 years of leadership.

Journal of Virology, January 2003, p. 433-442, Vol. 77, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.1.433-442.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.





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