Alphaherpesvirus US3-mediated reorganization of the actin cytoskeleton is mediated by group A p21-activated kinases
- Céline Van den Broekea,
- Maria Radub,
- Matthias Deruellea,
- Hans Nauwyncka,
- Clemens Hofmannb,
- Zahara M. Jafferb,
- Jonathan Chernoffb and
- Herman W. Favoreela,1
- aDepartment of Virology, Parasitology, and Immunology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium; and
- bFox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497
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Edited by Patricia G. Spear, Northwestern University Feinberg School of Medicine, Chicago, IL, and approved April 2, 2009 (received for review January 14, 2009)
Abstract
The US3 protein is a viral serine/threonine kinase that is conserved among all members of the Alphaherpesvirinae. The US3 protein of different alphaherpesviruses causes dramatic alterations in the actin cytoskeleton, such as the disassembly of actin stress fibers and formation of cell projections, which have been associated with increased intercellular virus spread. Here, we find that inhibiting group A p21-activated kinases (PAKs), which are key regulators in Cdc42/Rac1 Rho GTPase signaling pathways, impairs US3-mediated actin alterations. By using PAK1−/− and PAK2−/− mouse embryo fibroblasts (MEFs), we show that US3-mediated stress fiber disassembly requires PAK2, whereas US3-mediated cell projection formation mainly is mediated by PAK1, also indicating that PAK1 and PAK2 can have different biological effects on the organization of the actin cytoskeleton. In addition, US3 was found to bind and phosphorylate group A PAKs. Lack of group A PAKs in MEFs was correlated with inefficient virus spread. Thus, US3 induces its effect on the actin cytoskeleton via group A PAKs.
Footnotes
- 1To whom correspondence should be addressed. E-mail: Herman.Favoreel{at}UGent.be
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Author contributions: C.V.d.B., J.C., and H.W.F. designed research; C.V.d.B., M.R., and M.D. performed research; C.H. and Z.M.J. contributed new reagents/analytic tools; C.V.d.B., M.R., M.D., H.N., J.C., and H.W.F. analyzed data; and C.V.d.B., J.C., and H.W.F. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0900436106/DCSupplemental.
