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Journal of Virology, May 2009, p. 4778-4790, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02493-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Arginine Methylation of Human Adenovirus Type 5 L4 100-Kilodalton Protein Is Required for Efficient Virus Production{triangledown}

Orkide Ö. Koyuncu and Thomas Dobner*

Heinrich-Pette-Institute for Experimental Virology and Immunology, Martinistr. 52, 20251 Hamburg, Germany

Received 4 December 2008/ Accepted 24 February 2009

The adenovirus type 5 (Ad5) late region 4 (L4) 100-kDa nonstructural protein (L4-100K) mediates inhibition of cellular protein synthesis and selective translation of tripartite leader (TL)-containing viral late mRNAs via ribosome shunting. In addition, L4-100K has been implicated in the trimerization and nuclear localization of hexon protein. We previously proved that L4-100K is a substrate of the protein arginine methylation machinery, an emergent posttranslational modification system involved in a growing list of cellular processes, including transcriptional regulation, cell signaling, RNA processing, and DNA repair. As understood at present, L4-100K arginine methylation involves protein arginine methyltransferase 1 (PRMT1), which asymmetrically dimethylates arginines embedded in arginine-glycine-glycine (RGG) or glycine-arginine-rich (GAR) domains. To identify the methylated arginine residues and assess the role of L4-100K arginine methylation, we generated amino acid substitution mutations in the RGG and GAR motifs to examine their effects in Ad-infected and plasmid-transfected cells. Arginine-to-glycine exchanges in the RGG boxes significantly diminished L4-100K methylation in the course of an infection and substantially reduced virus growth, demonstrating that L4-100K methylation in RGG motifs is an important host cell function required for efficient Ad replication. Our data further indicate that PRMT1-catalyzed arginine methylation in the RGG boxes regulates the binding of L4-100K to hexon and promotes the capsid assembly of the structural protein as well as modulating TL-mRNA interaction. Furthermore, substitutions in GAR, but not RGG, regions affected L4-100K nuclear import, implying that the nuclear localization signal of L4-100K is located within the GAR sequence.

* Corresponding author. Mailing address: Heinrich-Pette-Institute for Experimental Virology and Immunology, Martinistr. 52, 20251 Hamburg, Germany. Phone: 49 040 48051 301. Fax: 49 040 48051 302. E-mail: thomas.dobner{at}hpi.uni-hamburg.de

{triangledown} Published ahead of print on 4 March 2009.

Journal of Virology, May 2009, p. 4778-4790, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02493-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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