Role of the Serine-Threonine Kinase PAK-1 in Myxoma Virus Replication
Open Access
- 15 May 2003
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 77 (10), 5877-5888
- https://doi.org/10.1128/jvi.77.10.5877-5888.2003
Abstract
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.Keywords
This publication has 46 references indexed in Scilit:
- Binding of FADD and Caspase-8 to Molluscum Contagiosum Virus MC159 v-FLIP Is Not Sufficient for Its Antiapoptotic FunctionJournal of Virology, 2002
- Phosphorylation of Raf-1 by Kinase Suppressor of Ras Is Inhibited by “MEK-Specific” Inhibitors PD 098059 and U0126 in Differentiating HL60 CellsExperimental Cell Research, 2001
- Vaccinia Virus Blocks Gamma Interferon Signal Transduction: Viral VH1 Phosphatase Reverses Stat1 ActivationJournal of Virology, 2001
- The Vaccinia Virus A33R Protein Provides a Chaperone Function for Viral Membrane Localization and Tyrosine Phosphorylation of the A36R ProteinJournal of Virology, 2001
- Immunomodulation by viruses: the myxoma virus storyImmunological Reviews, 1999
- Effect of SB 203580 on the activity of c-Raf in vitro and in vivoOncogene, 1999
- Activation of Raf-1 by Interferon γ and Oncostatin M Requires Expression of the Stat1 Transcription FactorPublished by Elsevier BV ,1998
- Human p21-activated kinase (Pak1) regulates actin organization in mammalian cellsCurrent Biology, 1997
- Inhibitory effect of tyrphostin on the replication of herpes simplex virus type 1Archiv für die gesamte Virusforschung, 1995
- Inhibition of Moloney murine leukemia virus replication by tyrphostins, tyrosine kinase inhibitorsFEBS Letters, 1994