Actin Filaments Disruption And Stabilization Affect Measles Virus Maturation By Different Mechanisms

Tuesday, 12th of November 2013

[source]Virology Journal[|source]

The actin network is primarily associated with mechanical stability, cell motility and cell contraction. It is also important for chromosome movement during mitosis and for internal transport, particularly near the plasma membrane. In measles virus infections, several reports have shown that actin is involved in virus maturation at the plasma membrane. This idea was initially based on the findings that actin was identified as an internal component of measles virus particles and co-caps with MV H on infected cells. Very recently, it was further proposed that F-actin associates with the MV M protein altering the interaction between M and H, hereby modulating MV cell-cell fusion and assembly.

In this report, the authors analyze the effects of actin-disrupting and actin-stabilizing drugs to define if actin filaments as structural components or rather actin dynamics and tread milling are essential for MV maturation. The article demonstrates that intact actin filaments are required for M-RNP transport to the plasma membrane, and are thus needed to initiate assembly at the plasma membrane and to down regulate cell-to-cell fusion mediated by surface-expressed viral glycoproteins. The authors further provide the first conclusive evidence that actin dynamics are critically required in later steps in MV maturation, particularly for bud formation and the final pinching-off. The article also postulates the high likelihood that integrity and dynamics of actin filaments not only play an important role in virus maturation at the plasma membrane, but are also involved in MV-mediated immunosuppression. More details are available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750272/

Abstract

Background: Cytoskeletal proteins are often involved in the virus life cycle, either at early steps during virus entry or at later steps during formation of new virus particles. Though actin filaments have been shown to play a role in the production of measles virus (MV), the importance of actin dynamics for virus assembly and budding steps is not known yet. Aim of this work was thus to analyze the distinctive consequences of F-actin stabilization or disruption for MV protein trafficking, particle assembly and virus release.

Results: MV infection studies in the presence of inhibitors differently affecting the actin cytoskeleton revealed that not only actin disruption but also stabilization of actin filaments interfered with MV particle release. While overall viral protein synthesis, surface expression levels of the MV glycoproteins, and cell-associated infectivity was not altered, cell-free virus titres were decreased. Interestingly, the underlying mechanisms of interference with late MV maturation steps differed principally after F-actin disruption by Cytochalasin D (CD) and F-actin stabilization by Jasplakinolide (Jaspla). While intact actin filaments were shown to be required for transport of nucleocapsids and matrix proteins (M-RNPs) from inclusions to the plasma membrane, actin dynamics at the cytocortex that are blocked by Jaspla are necessary for final steps in virus assembly, in particular for the formation of viral buds and the pinching-off at the plasma membrane. Supporting our finding that F-actin disruption blocks M-RNP transport to the plasma membrane, cell-to-cell spread of MV infection was enhanced upon CD treatment. Due to the lack of M-glycoprotein-interactions at the cell surface, M-mediated fusion down regulation was hindered and a more rapid syncytia formation was observed.

Conclusion: While stable actin filaments are needed for intracellular trafficking of viral RNPs to the plasma membrane, and consequently for assembly at the cell surface and prevention of an overexerted fusion by the viral surface glycoproteins, actin dynamics are required for the final steps of budding at the plasma membrane.