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Journal of Virology, May 2003, p. 5877-5888, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5877-5888.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Role of the Serine-Threonine Kinase PAK-1 in Myxoma Virus Replication

J. B. Johnston,1 John W. Barrett,1 Wen Chang,2 Che-Sheng Chung,2 Wei Zeng,1 Jennefer Masters,1 Melissa Mann,1 Fuan Wang,1 Jingxin Cao,1,{dagger} and Grant McFadden1*

Robarts Research Institute and Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada N6G 2V4,1 Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan 1152

Received 20 November 2002/ Accepted 20 February 2003

Subversion or appropriation of cellular signal transduction pathways is a common strategy employed by viruses to promote an environment within infected cells that supports the viral replicative cycle. Using subsets of 3T3 murine fibroblasts previously shown to differ in their ability to support myxoma virus (MV) replication, we investigated the role of host serine-threonine kinases (STKs) as potential mediators of the permissive phenotype. Both permissive and nonpermissive 3T3 cells supported equivalent levels of virion binding, entry, and early virus gene expression, indicating that MV tropism in 3T3 cells was not determined by receptor-mediated entry. In contrast, late virus gene expression and viral DNA replication were selectively compromised in restrictive 3T3 cells. Addition of specific protein kinase inhibitors, many of which shared the ability to influence the activity of the STKs p21-activated kinase 1 (PAK-1) and Raf-1 attenuated MV replication in permissive 3T3 cells. Western blot detection of the phosphorylated forms of PAK-1 (Thr423) and Raf-1 (Ser338) confirmed activation of these kinases in permissive cells after MV infection or gamma interferon treatment, but the activated forms of both kinases were greatly reduced or absent in restrictive 3T3 cells. The biological significance of these activations was demonstrated by using the autoinhibitory domain of PAK-1 (amino acids 83 to 149), expression of which reduced the efficiency of MV infection in permissive 3T3 cells concurrent with a decrease in PAK-1 activation. In comparison, overexpression of a constitutively active PAK-1 (T423E) mutant increased MV replication in restrictive 3T3 cells. These observations suggest that induced signaling via cellular STKs may play important roles in determining the permissiveness of host cells to poxvirus infection.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, The University of Western Ontario, 1400 Western Rd., London, Ontario, Canada N6G 2V4. Phone: (519) 663-3184. Fax: (519) 663-3847. E-mail: mcfadden{at}robarts.ca.

{dagger} Present address: National Microbiology Laboratory, Health Canada, Winnipeg, Manitoba, Canada R3E 3R2.

Journal of Virology, May 2003, p. 5877-5888, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5877-5888.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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