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Vol. 17, Issue 7, 3329-3344, July 2006

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Adenovirus E4orf4 Hijacks Rho GTPase-dependent Actin Dynamics to Kill Cells: A Role for Endosome-associated Actin Assembly

Amélie Robert^*, Nicolas Smadja-Lamère^*, Marie-Claude Landry^*, Claudia Champagne^*, Ryan Petrie, Nathalie Lamarche-Vane, Hiroshi Hosoya, and Josée N. Lavoie^*

*Centre de Recherche en Cancérologie de l’Université Laval, L’Hôtel-Dieu de Québec, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, Québec G1R 2J6, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, Québec H3A 2B2, Canada; and Department of Biological Science, Graduate School of Science, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8526, Japan

Submitted December 16, 2005; Revised April 12, 2006; Accepted April 27, 2006
Monitoring Editor: J. Silvio Gutkind

The adenovirus early region 4 ORF4 protein (E4orf4) triggers a novel death program that bypasses classical apoptotic pathways in human cancer cells. Deregulation of the cell cytoskeleton is a hallmark of E4orf4 killing that relies on Src family kinases and E4orf4 phosphorylation. However, the cytoskeletal targets of E4orf4 and their role in the death process are unknown. Here, we show that E4orf4 translocates to cytoplasmic sites and triggers the assembly of a peculiar juxtanuclear actin–myosin network that drives polarized blebbing and nuclear shrinkage. We found that E4orf4 activates the myosin II motor and triggers de novo actin polymerization in the perinuclear region, promoting endosomes recruitment to the sites of actin assembly. E4orf4-induced actin dynamics requires interaction with Src family kinases and involves a spatial regulation of the Rho GTPases pathways Cdc42/N-Wasp, RhoA/Rho kinase, and Rac1, which make distinct contributions. Remarkably, activation of the Rho GTPases is required for induction of apoptotic-like cell death. Furthermore, inhibition of actin dynamics per se dramatically impairs E4orf4 killing. This work provides strong support for a causal role for endosome-associated actin dynamics in E4orf4 killing and in the regulation of cancer cell fate.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Josée N. Lavoie ( josee.lavoie{at}crhdq.ulaval.ca)

Abbreviations used: Ad2 E4orf4, adenovirus type 2 early region 4 open reading frame 4; SFK, Src family kinase; ROCK, Rho-kinase; PP2A, protein phosphatase 2A; MLC, myosin-II light chain; pCRIB, Cdc42/Rac interactive binding domain of Pak; wCRIB, N-Wasp CRIB; rRBD, Rho binding domain of ROCK; rhotRBD, RBD of Rhotekin; ScarVCA, Verprolin homology, Central and Acidic domains of Scar1; MYPT, target subunit of MLCP; cytoD, cytochalasin D; EV, empty vector; mRFP, monomeric red fluorescent protein; GalT, -1,4-galactosyl transferas; BFA, brefeldin A; Tf, transferrin; TfR, transferrin receptor; GPI, glycosylphosphatidylinositol; RE, recycling endocytic compartment.

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