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Journal of Virology, June 2008, p. 6009-6016, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.00280-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Mutagenesis of the Active-Site Cysteine in the Ubiquitin-Specific Protease Contained in Large Tegument Protein pUL36 of Pseudorabies Virus Impairs Viral Replication In Vitro and Neuroinvasion In Vivo {triangledown}

Sindy Böttcher,1,{dagger} Christina Maresch,1,{dagger} Harald Granzow,2 Barbara G. Klupp,1 Jens P. Teifke,2 and Thomas C. Mettenleiter1*

Institutes of Molecular Biology,1 Infectology, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany2

Received 7 February 2008/ Accepted 2 April 2008

Herpesviruses specify a ubiquitin-specific protease activity located within their largest tegument protein. Although its biological role is still largely unclear, mutation within the active site abolished deubiquitinating (DUB) activity and decreased virus replication in vitro and in vivo. To further elucidate the role of DUB activity for herpesvirus replication, the conserved active-site cysteine at amino acid position 26 within pUL36 of Pseudorabies virus (PrV) (Suid herpesvirus 1), a neurotropic alphaherpesvirus, was mutated to serine. Whereas one-step growth kinetics of the resulting mutant virus PrV-UL36(C26S) were moderately reduced, plaque size was decreased to 62% of that of the wild-type virus. Ultrastructural analysis revealed large accumulations of unenveloped nucleocapsids in the cytoplasm, but incorporation of the tegument protein pUL37 was not abolished. After intranasal infection with PrV-UL36(C26S) mice showed survival times two times longer than those of mice infected with wild-type or rescued virus. Thus, the DUB activity is important for PrV replication in vitro and for neuroinvasion in mice.

* Corresponding author. Mailing address: Friedrich-Loeffler-Institut, Institute of Molecular Biology, Südufer 10, 17493 Greifswald-Insel Riems, Germany. Phone: 49-38351-7250. Fax: 49-38351-7151. E-mail: thomas.mettenleiter{at}fli.bund.de

{triangledown} Published ahead of print on 9 April 2008.

{dagger} Contributed equally to this work.

Journal of Virology, June 2008, p. 6009-6016, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.00280-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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