Key Points
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Actin is a ubiquitous cellular protein that forms a foundation for cellular structure and integrity. Viruses are obligate intracellular parasites with a replication cycle that requires them to engage and modify the actin cytoskeleton at all stages, from entry through replication to egress and spread.
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Oncogenic proteins of transforming viruses interfere with the RHO-family GTPases (actin-signalling molecules) to change cellular dynamics from a quiescent to a mitotic state. The actin cytoskeleton is altered dramatically, cell shape changes, and cell-to-cell contact and matrix adhesion are lost, while podosomes and membrane ruffles appear on the cell surface.
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Virus-mediated oncogenic transformation can result in metastatic tumours in humans, such as nasopharyngeal, hepatocellular and cervical carcinomas (induced by Epstein–Barr virus, hepatitis B virus and human papillomavirus, respectively). In vitro, viral proteins increase cell migration by disrupting and modulating actin dynamics. The host proteins involved in these interactions may be specific cytoskeletal targets for antimetastatic therapies.
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Virions often interact with the underlying actin cytoskeleton to gain entry to the cell. Virions may move to entry sites using high-affinity interactions with receptors that are associated with actin filaments inside the cell. Movement is promoted by myosin motors that drive the actin cytoskeleton, pulling the receptor–virion complex across the plasma membrane. Virion entry by endocytic processes or formation of the fusion pore also often involves cortical actin.
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Actin structures can be modified during viral infection to produce long cellular extensions (for example, filopodia and tunnelling nanotubes). These structures facilitate the long-distance dissemination of a wide range of viruses, including vaccinia virus, herpes simplex viruses, HIV and rotaviruses.
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Most actin–virus interactions have been discovered in isolated or cultured cell systems. The next generation of research will apply this knowledge to viral infections in vivo to understand the role of viral subversion of the actin cytoskeleton in disease.
Abstract
Viral infection converts the normal functions of a cell to optimize viral replication and virion production. One striking observation of this conversion is the reconfiguration and reorganization of cellular actin, affecting every stage of the viral life cycle, from entry through assembly to egress. The extent and degree of cytoskeletal reorganization varies among different viral infections, suggesting the evolution of myriad viral strategies. In this Review, we describe how the interaction of viral proteins with the cell modulates the structure and function of the actin cytoskeleton to initiate, sustain and spread infections. The molecular biology of such interactions continues to engage virologists in their quest to understand viral replication and informs cell biologists about the role of the cytoskeleton in the uninfected cell.
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Acknowledgements
The authors acknowledge M. Way, W. Bohn, K. Gruenwald and K. DeMali for generously providing the original electron micrographs. They also appreciate the guidance and encouragement from all members of the Enquist laboratory. L.W.E. and O.O.K. are supported by the US National Institutes of Health grants R37 NS033506-16 and R01 NS060699-03. M.P.T. is supported by an American Cancer Society Postdoctoral Research Fellowship (PF-10-057-01-MPC).
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Glossary
- Gelsolin
-
A calcium-activated protein that severs actin filaments.
- Lamellipodia
-
Wide, thin sheets of membrane extending from the cell body; lamellipodia are often associated with the leading edge of motile cells.
- Membrane ruffles
-
Membrane-enclosed, densely packed actin bundles that increase during cell migration or transformation. Ruffles localize to the leading edge of the lamellipodia, giving these structures a flower-like appearance.
- Filopodia
-
Long, thin membranous extensions of the cell with a core of actin filaments.
- Podosomes
-
Dot-like extracellular matrix attachment sites in motile cells. In transformed cells, podosomes aggregate in the presence of serum to form ring- or crescent-shaped rosettes.
- Pseudopodia
-
Large membranous protrusions that are used to promote the movement of highly motile cells; the name is derived from the Greek for 'false-footed'.
- Contact inhibition
-
The inhibition of uncontrolled cell division by cell–cell contact through mitogen-activated protein kinase signalling. Contact inhibition is deregulated in transformed cell populations.
- Adherens junctions
-
Epithelial cell-to-cell junctions that connect the actin cytoskeleton of one cell to the cytoplasm of the neighbouring cell via cadherins and catenins.
- Vinculin
-
A focal-adhesion plaque protein that is associated with the microfilament ends and talin.
- Talin
-
An actin-binding protein associated with adherens junctions, ruffling membranes and other sites of actin–membrane interaction.
- α-actinin
-
A large family of proteins that crosslink and bundle actin filaments in a calcium-dependent manner in non-muscle cells.
- Focal adhesions
-
Macromolecular complexes that connect the actin cytoskeleton to the extracellular matrix by the association of transmembrane integrins with extracellular proteins such as fibronectin.
- Caldesmon
-
A calmodulin-binding and F-actin-binding protein that regulates the function of actin filaments in a calcium-dependent manner.
- Clathrin-mediated endocytosis
-
The process of enveloping extracellular material and bringing it into the cellular cytoplasm within a membranous vesicle. Invagination of the plasma membrane and stabilization of the vesicle is carried out by triskelions of clathrin that polymerize at the membrane surface to induce curvature.
- Macropinocytosis
-
A specialized form of endocytosis that is used by the cell to obtain soluble materials from the extracellular environment.
- Actin treadmilling
-
The act of moving a specific actin monomer, or its position, along an actin filament using active polymerization and depolymerization processes.
- Comet tails
-
Dense structures of actin filaments that are used to propel objects through the cytoplasm or long distances away from the cell.
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Taylor, M., Koyuncu, O. & Enquist, L. Subversion of the actin cytoskeleton during viral infection. Nat Rev Microbiol 9, 427–439 (2011). https://doi.org/10.1038/nrmicro2574
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DOI: https://doi.org/10.1038/nrmicro2574
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